Substituted azabicyclic compounds

ABSTRACT

This invention is directed to physiologically active compounds of formula (I)  
                 
 
wherein  
                 
 
represents a bicyclic ring system, of about 10 to about 13 ring members, in which the ring  
                 
 
is an azaheterocycle, and the ring  
                 
represents an azaheteroaryl ring, or an optionally halo substituted benzene ring; 
         R 1  represents hydrogen or a straight- or branched-chain alkyl group of 1 to about 4 carbon atoms, optionally substituted by hydroxy or one or more halogen atoms, or when Z 1  represents a direct bond R 1  may also represent a lower alkenyl or lower alkynyl group, or a formyl group;    R 2  represents hydrogen, alkenyl, alkoxy, alkyl, alkylsulphinyl, alkylsulphonyl, alkylthio, aryl, arylalkyloxy, arylalkylsulphinyl, arylalkylsulphonyl, arylalkylthio, aryloxy, arylsulphinyl, arylsulphonyl, arylthio, cyano, cycloalkenyl, cycloalkenyloxy, cycloalkyl, cycloalkyloxy, heteroaryl, heteroarylalkyloxy, heteroaryloxy, hydroxy, —SO 2 NR 4 R 5 , —NR 4 SO 2 R 5 , —NR 4 R 5 , —C(═O)R 5 , —C(═O)C(═O)R 5 , —C(═O)NR 4 R 5 , —C(═O)OR 5 , —O(C═O)NR 4 R 5 , or —NR 4 C(═O)R 5 ;    R 3  represents —C(=Z)—N(R 7 )R 6 , —C(=Z)—CHR 12 R 6 , —C(=Z)—R 6 , —CR 8 ═C(R 9 )(CH 2 ) p —R 6 , —C(R 10 )═C(R 11 )R 12 , —C(R 13 )(R 10 )C(R 11)(R   14 )R 12 , —C(R 8 )(R 15 )CH(R 9 )(CH 2 ) p —R 6 , —R 6 , —N(R 16 )C(=Z)R 6 , —C(R 17 )═N—OC(= 0 )R 18 , —C(═O)—N(R 19 )OR 20 , —C≡C—R 6 , —CH 2 —C(=Z)—R 6 , —C(=Z)—C(=Z)R 6 , —CH 2 —NHR 6 , —CH 2 -ZR 6 , —CH 2 —SOR 6 , —CH 2 —SO 2 R 6 , —CF 2 —OR 6 , —NH—CH 2 R 6 , -Z-CH 2 R 6 , —SO—CH 2 R 6 , —SO 2 —CH 2 R 6 , —O—CF 2 R 6 , —O—C(=Z)R 6 , —N═N—R 6 , —NH—SO 2 R 6 , —SO 2 —NR 21 R 22 , —CZ-CZ-NHR 6 , —NH—CO—OR 6 , —O—CO—NHR 6 , —NH—CO—NHR 6 , —R 23 , —CX 1 ═CX 2 R 6 , —C(═NOR 24 ), —(CH 2 ) q R 6 , —CH 2 —CO—NH(CH 2 ) q R 6 , —CH 2 —NH—CO(CH 2 ) q R 6 , —CH 2 —CO—CH 2 R 6 , —C(═NR 25 )—NH(CH 2 ) q R 6 , —C(X 3 )═N—(CH 2 ) q R 6  or —CH(X 4 )—CH 2 R 6 ;    A 1  represents a direct bond, or a straight or branched C 1-6  alkylene chain optionally substituted by hydroxyl, alkoxy, oxo, cycloalkyl, aryl or heteroaryl, or A 1  represents a straight or branched C 2-6 alkenylene or C 2-6 alkynylene chain;    Z 1  represents a direct bond, an oxygen or sulphur atom or NH; n and m each represent zero or 1, provided that n is 1 when m is zero and n is zero when m is 1; and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (I) and N-oxides thereof, and their prodrugs. Such compounds inhibit the production or physiological effects of TNF and inhibit cyclic AMP phosphodiesterase. The invention is also directed to pharmaceutical compositions comprising compounds of formula (I), their pharmaceutical use and methods for their preparation.

This application is a continuation application of U.S. patentapplication Ser. No. 09/216,392, filed Dec. 18, 1998, which is acontinuation application of International Patent Application No.PCT/GB97/01639, filed Jun. 19, 1999, which application, in turn, is acontinuation-in-part application of U.S. provisional patent applicationNo. 60/023,047, filed Aug. 2, 1996, now abandoned.

This invention is directed to substituted azabicyclic compounds, theirpreparation, pharmaceutical compositions containing these compounds, andtheir pharmaceutical use in the treatment of disease states associatedwith proteins that mediate cellular activity.

Tumour necrosis factor (TNF) is an important pro-inflammatory cytokinewhich causes hemorrhagic necrosis of tumors and possesses otherimportant biological activities. TNF is released by activatedmacrophages, activated T-lymphocytes, natural killer cells, mast cellsand basophils, fibroblasts, endothelial cells and brain astrocytes amongother cells.

The principal in vivo actions of TNF can be broadly classified asinflammatory and catabolic. It has been implicated as a mediator ofendotoxic shock, inflammation of joints and of the airways, immunedeficiency states, allograft rejection, and in the cachexia associatedwith malignant disease and some parasitic infections. In view of theassociation of high serum levels of TNF with poor prognosis in sepsis,graft versus host disease and adult respiratory distress syndrome, andits role in many other immunologic processes, this factor is regarded asan important mediator of general inflammation.

TNF primes or activates neutrophils, eosinophils, fibroblasts andendothelial cells to release tissue damaging mediators. TNF alsoactivates monocytes, macrophages and T-lymphocytes to cause theproduction of colony stimulating factors and other pro-inflammatorycytokines such IL₁, IL₆, IL₈ and GM-CSF, which in some case mediate theend effects of TNF. The ability of TNF to activate T-lymphocytes,monocytes, macrophages and related cells has been implicated in theprogression of Human immunodeficiency Virus (HIV) infection. In orderfor these cells to become infected with HIV and for HIV replication totake place the cells must be maintained in an activated state. Cytokinessuch as TNF have been shown to activate HIV replication in monocytes andmacrophages. Features of endotoxic shock such as fever, metabolicacidosis, hypotension and intravascular coagulation are thought to bemediated through the actions of TNF on the hypothalamus and in reducingthe anti-coagulant activity of vascular endothelial cells. The cachexiaassociated with certain disease states is mediated through indirecteffects on protein catabolism. TNF also promotes bone resorption andacute phase protein synthesis.

The discussion herein relates to disease states associated with TNFincluding those disease states related to the production of TNF itself,and disease states associated with other cytokines, such as but notlimited to IL-1, or IL-6, that are modulated by associated with TNF. Forexample, a IL-1 associated disease state, where IL-1 production oraction is exacerbated or secreted in response to TNF, would therefore beconsidered a disease state associated with TNF. TNF-alpha and TNF-betaare also herein referred to collectively as “TNF” unless specificallydelineated otherwise, since there is a close structural homology betweenTNF-alpha (cachectin) and TNF-beta (lymphotoxin) and each of them has acapacity to induce similar biological responses and bind to the samecellular receptor.

Cyclic AMP phosphodiesterases are important enzymes which regulatecyclic AMP levels and in turn thereby regulate other importantbiological reactions. The ability to regulate cyclic AMPphosphodiesterases therefore, has been implicated as being capable oftreating assorted biological conditions. In particular, inhibitors oftype IV cyclic AMP phosphodiesterase have been implicated as beingbronchodilators agents, prophylactic agents useful against asthma and asagents for inhibiting eosinophil accumulation and of the function ofeosinophils, and for treating other diseases and conditionscharacterised by, or having an etiology involving, morbid eosinophilaccumulation. Inhibitors of cyclic AMP phosphodiesterase are alsoimplicated in treating inflammatory diseases, proliferative skindiseases and conditions associated with cerebral metabolic inhibition.

It has already been reported that certain substituted monocyclicaromatic compounds have valuable pharmaceutical properties, inparticular the ability to regulate proteins that mediate cellularactivity, for example, type IV cyclic AMP phosphodiesterase and/or TNF,as described, for example, in the specification of International PatentApplication Publication No. WO 95/04045.

Certain substituted bicyclic aromatic compounds, for exampleamino-substituted benzofurans and benzothiophenes, are reported inEuropean Patent Application EP-A-0685475, to have the ability toregulate elevated cellular cyclic AMP levels probably due to inhibitionof type IV cyclic AMP phosphodiesterase.

Further examples of substituted bicyclic aromatic compounds with type IVcyclic AMP phosphodiesterase and/or TNF inhibitory activity includedihydrobenzofurans reported in WO 96/36625 and WO 96/36626.

We have now found a novel group of azabicyclic compounds which havevaluable pharmaceutical properties, in particular the ability toregulate proteins that mediate cellular activity, for example, cyclicAMP phosphodiesterases (in particular type IV) and/or TNF.

Thus, in one aspect, the present invention is directed to compounds ofgeneral formula (I):-

wherein

represents a bicyclic ring system, of about 10 to about 13 ring members,in which the ring

is an azaheterocycle, and the ring

represents an azaheteroaryl ring, or an optionally halo substitutedbenzene ring;

-   -   R¹ represents hydrogen or a straight- or branched-chain alkyl        group of 1 to about 4 carbon atoms, optionally substituted by        hydroxy or one or more halogen atoms, or when Z¹ represents a        direct bond R¹ may also represent a lower alkenyl or lower        alkynyl group, or a formyl group;    -   R² represents hydrogen, alkenyl, alkoxy, alkyl, alkylsulphinyl,        alkylsulphonyl, alkylthio, aryl, arylalkyloxy,        arylalkylsulphinyl, arylalkylsulphonyl, arylalkylthio, aryloxy,        arylsulphinyl, arylsulphonyl, arylthio, cyano, cycloalkenyl,        cycloalkenyloxy, cycloalkyl, cycloalkyloxy, heteroaryl,        heteroarylalkyloxy, heteroaryloxy, hydroxy, —SO₂NR⁴R⁵,        —NR⁴SO₂R⁵, —NR⁴R⁵, —C(═O)R⁵, —C(═O)C(═O)R⁵, —C(═O)NR⁴R⁵,        —C(═O)OR⁵, —O(C═O)NR⁴R⁵, or —NR⁴C(═O)R⁵ (where R⁴ and R⁵, which        may be the same or different, each represent a hydrogen atom, or        an alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or        heteroarylalkyl group);    -   R³ represents a group selected from:    -   (i) —C(=Z)—N(R⁷)R⁶    -   (ii) —C(=Z)—CHR¹²R⁶    -   (iii) —C(=Z)—R⁶    -   (iv) —CR⁸═C(R⁹)(CH₂)_(p)—R⁶    -   (v) —C(R¹⁰)═C(R¹¹)R¹²    -   (vi) —C(R¹³)(R¹⁰)C(R¹¹)(R¹⁴)R¹²    -   (vii) —C(R⁸)(R¹⁵)CH(R⁹)(CH₂)_(p)—R⁶    -   (viii) —R⁶    -   (ix) —N(R¹⁶)C(=Z)R⁶    -   (x) —C(R¹⁷)═N—OC(=0)R¹⁸    -   (xi) —C(═O)—N(R¹⁹)OR²⁰    -   (xii) —C≡C—R⁶    -   (xiii) —CH₂—C(=Z)—R⁶    -   (xiv) —C(=Z)—C(=Z)R⁶    -   (xv) —CH₂—NHR⁶    -   (xvi) —CH₂-ZR⁶    -   (xvii) —CH₂—SOR⁶    -   (xviii) —CH₂—SO₂R⁶    -   (xix) —CF₂—OR⁶    -   (xx) —NH—CH₂R⁶    -   (xxi) -Z-CH₂R⁶    -   (xxii) —SO—CH₂R⁶    -   (xxiv) —SO₂—CH₂R⁶    -   (xxv) —O—CF₂R⁶    -   (xxiii) —O—C(=Z)R⁶    -   (xxvi) —N═N—R⁶    -   (xxvii) —NH—SO₂R⁶    -   (xxviii) —SO₂—NR²¹R²²    -   (xxix) —CZ-CZ-NHR⁶    -   (xxx) —NH—CO—OR⁶    -   (xxxi) —O—CO—NHR⁶    -   (xxxii) —NH—CO—NHR⁶    -   (xxxiii) —R²³    -   (xxxiv) —CX¹═CX²R⁶    -   (xxxv) —C(═NOR²⁴)—(CH₂)_(q)R⁶    -   (xxxvi) —CH₂—CO—NH(CH₂)_(q)R⁶    -   (xxxvii) —CH₂—NH—CO(CH₂)_(q)R⁶    -   (xxxviii) —CH₂—CO—CH₂R⁶    -   (xxxix) —C(═NR²⁵)—NH(CH₂)_(q)R⁶    -   (xxxx) —C(X³)═N—(CH₂)_(q)R⁶    -   (xxxxi) —CH(X⁴)—CH₂R⁶        [where:

-   R⁶ is aryl or heteroaryl;

-   R⁷ is a hydrogen atom or an alkyl or amino group;

-   R⁸ and R⁹, which may be the same or different, is each a hydrogen    atom or alkyl, —CO₂R⁵, —C(=Z)NR²⁶R²⁷ (where R²⁶ and R²⁷ may be the    same or different and each is as described for R⁵), —CN or —CH₂CN;

-   R¹⁰ and R¹¹, which may be the same or different, is each a group    —(CH₂)_(p)R⁶;

-   R¹² is a hydrogen atom or an alkyl group;

-   R¹³ is a hydrogen or halogen atom or an —OR²⁸ group (where R²⁸ is a    hydrogen atom or an alkyl, alkenyl, alkoxyalkyl, acyl, carboxamido    or thiocarboxamido group);

-   R¹⁴ is a hydrogen atom or an alkyl group;

-   R¹⁵ is a hydrogen atom or a hydroxyl group;

-   R¹⁶ is a hydrogen atom or an alkyl, amino, aryl, arylalkyl, or    hydroxy group;

-   R¹⁷ is a hydrogen atom or a C₁₋₄alkyl or arylC₁₋₄alkyl group;

-   R¹⁸ is an amino, alkylamino, arylamino, alkoxy or aryloxy group;

-   R¹⁹ is an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl    group;

-   R²⁰ is R⁵, (CH₂)_(p)CO₂R⁵ or (CH₂)_(p)COR⁵;

-   R²¹ is a group -L¹-R²⁹ [where L¹ is a straight or branched    C₁₋₆alkylene chain, a straight or branched C₂₋₆alkenylene chain, a    straight or branched C₂₋₆alkynylene chain or a straight or branched    C₁₋₆alkylene chain containing an oxygen or sulphur atom, a    phenylene, imino (—NH—) or alkylimino linkage, or a sulphinyl or    sulphonyl group, in which each of the alkylene, alkenylene and    alkynylene chains may be optionally substituted, the substituents    chosen from alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen,    heteroaryl, hydroxyl or oxo; and R²⁹ is hydrogen, or    arylalkoxycarbonyl, carboxy or an acid bioisostere, cyano, —NY¹Y²,    {where Y¹ and Y² are independently hydrogen, alkyl, aryl, arylalkyl,    heterocycloalkyl, heteroaryl or heteroarylalkyl, or the group —NY¹Y²    may form a 4-6 membered cyclic amine (which may optionally contain a    further heteroatom selected from O, S, or NY¹, or which may be fused    to an additional aromatic or heteroaromatic ring)}], or R²¹ is an    optionally substituted cycloalkyl, cycloalkenyl or heterocycloalkyl    group which may optionally be fused to an additional optionally    substituted aromatic, heteroaromatic, carbocyclic or    heterocycloalkyl ring (where the one or more optional substituents,    for either or both rings, may be represented by -L¹-R²⁹);

R²² is a hydrogen atom, a group -L¹-R²⁹, or an optionally substitutedaryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl groupwhich may optionally be fused to an additional optionally substitutedaromatic, heteroaromatic, carbocyclic or heterocycloalkyl ring (wherethe one or more optional substituents, for either or both rings, may berepresented by -L¹-R²⁹); or both R²¹ and R²² represent aryl orheteroaryl each optionally substituted by -L¹-R²⁹; or the group —NR²¹R²²represents an optionally substituted saturated or unsaturated 3 to 8membered cyclic amine ring, which may optionally contain one or moreheteroatoms selected from O, S or N, and may also be fused to anadditional optionally substituted aromatic, heteroaromatic, carbocyclicor heterocycloalkyl ring (where the one or more optional substituents,for any of the rings, may be represented by -L¹-R²⁹);

{where:

-   R³⁰ is a hydrogen atom or an alkyl, hydroxyalkyl or alkoxyalkyl    group;-   R³¹ is a hydrogen atom or an alkyl, carboxy, CONHOR¹⁴,    N-alkylaminoalkyl, N,N-dialkylaminoalkyl or alkoxyalkyl group; or    R³⁰ and R³¹ together represent a —CH₂—O—CH₂—O—CH₂— group;-   R³² is a hydrogen atom, or amino, alkyl, aminoalkyl, hydroxyalkyl,    hydroxy, acyl, alkoxycarbonyl, methoxycarbonylalkyl,    —(CH₂)_(p)CONY³Y⁴ (where Y³ and Y⁴ are each independently hydrogen    or alkyl), —(CH₂)_(p)SO₂NY³Y⁴, —(CH₂)_(p)PO₃H₂,    —(CH₂)_(p)SO₂NHCOalkyl, or —(CH₂)_(p)SO₂NHCOR⁶;-   R³³ is C₁₋₄alkyl, CH₂NHCOCONH₂, CH═C(R⁴³)R⁴⁴ (where R⁴³ is R⁴⁴ or    fluorine and R⁴⁴ is hydrogen or C₁₋₄alkyl optionally substituted by    1 to 3 fluorine atoms), cyclopropyl (optionally substituted by R⁴³),    CN, CH₂OR⁴⁴ or CH₂NR⁴⁴R⁴⁵ (where R⁴⁵ is hydrogen, OR⁴⁴, or C₁₋₄alkyl    optionally substituted by 1 to 3 fluorine atoms, or the group    NR⁴⁴R⁴⁵ represents a 5 to 7 membered cyclic amine optionally    containing one or more additional heteroatom selected from O, N, or    S);-   R³⁴ is methyl or ethyl optionally substituted by 1 or more halogen    atoms;-   R³⁵ is R¹⁴, —OR¹⁴, —CO₂R¹⁴, —COR¹⁴, —CN, —CONY³Y⁴ or —NY³Y⁴;-   R³⁶ is —C(=Z)R¹⁴, —CO₂R¹⁴, —CONY³Y⁴ or —CN;-   R³⁷ and R³⁹, which may be the same or different, is each a hydrogen    atom, alkyl, acyl, arylalkyl, —(CH₂)_(p)CO₂R⁵, —CONHR⁵,    heteroarylalkyl, aryl, or heteroaryl;-   R³⁸ is acyl, aroyl, —C(═O)cycloalkyl, alkoxycarbonyl,    cycloalkoxycarbonyl, carboxy, alkoxyalkyl, —NO₂, —CH₂OH, —CN,    —NR¹⁴COR⁵, —NR¹⁴CONY⁵Y⁶, —NR¹⁴SO₂R⁴⁶ [where R⁴⁶ is alkyl,    cycloalkyl, trifluoromethyl, aryl, arylalkyl or —NY⁵Y⁶ (where Y⁵ and    Y⁶ are independently selected from hydrogen, alkyl, cycloalkyl, aryl    or arylalkyl, or Y⁵ and Y⁶ together form a 4- to 7-membered    heterocyclic or carbocyclic ring)], —SO₂R⁴⁶ or —CONY⁵Y⁶;-   R⁴⁰ is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, acyl, aroyl,    —C(═O)cycloalkyl, —CH₂OH, alkoxyalkyl, alkoxycarbonyl,    cycloalkoxycarbonyl, aryloxycarbonyl, —CN, —NO₂, or —SO₂R⁴⁶;-   R⁴¹ is —CN, —C(Z)R⁴⁷ (where R⁴⁷ is hydrogen, alkyl, haloalkyl,    cycloalkyl, aryl, arylalkyl, heteroaryl, C₁₋₆alkoxy, arylalkoxy,    aryloxy or —NY⁵Y⁶) or SO₂R⁴⁶;-   R⁴² is hydrogen, alkyl, cycloalkyl, acyl, aroyl, —C(═O)cycloalkyl,    alkoxycarbonyl, cycloalkoxycarbonyl, carboxy, —CN, —SO₂R⁴⁶ or    —CONY⁵Y⁶;-   W is (CH₂)_(r) or NR³⁹;-   Z³ is an oxygen atom, NR¹⁴ or NOR¹⁴;-   s is zero or an integer 1 to 4;-   r is 1 to 4; and-   Y is an oxygen atom, C(═O), CH(OH) or C(OR¹⁴)(CH₂)_(p)R⁶};-   R²⁴ is R⁵ or CONHR²⁵;-   R²⁵ is hydrogen, C₁₋₃alkyl or (CH₂)_(q)R⁶;-   p is zero or an integer 1 to 5;-   q is zero or 1;-   X¹ and X², which may be the same or different, is each a hydrogen or    fluorine atom;-   X³ is a chlorine or fluorine atom, alkoxy, aryloxy, heteroaryloxy,    arylalkyloxy or heteroarylalkyl;-   X⁴ is a halogen atom or hydroxy;-   Z represents an oxygen or sulphur atom];    -   A¹ represents a direct bond, or a straight or branched        C₁₋₆alkylene chain optionally substituted by hydroxyl, alkoxy,        oxo, cycloalkyl, aryl or heteroaryl, or A¹ represents a straight        or branched C₂₋₆alkenylene or C₂₋₆alkynylene chain;    -   Z¹ represents a direct bond, an oxygen or sulphur atom or NH;    -   n and m each represent zero or 1, provided that n is 1 when m is        zero and n is zero when m is 1;    -   and N-oxides thereof, and their prodrugs, and pharmaceutically        acceptable salts and solvates (e.g. hydrates) of the compounds        of formula (I) and N-oxides thereof, and their prodrugs.

In the present specification, the term “compounds of the invention”, andequivalent expressions, are meant to embrace compounds of generalformula (I) as hereinbefore described, which expression includes theN-oxides, the prodrugs, the pharmaceutically acceptable salts, and thesolvates, e.g. hydrates, where the context so permits. Similarly,reference to intermediates, whether or not they themselves are claimed,is meant to embrace their N-oxides, salts, and solvates, where thecontext so permits. For the sake of clarity, particular instances whenthe context so permits are sometimes indicated in the text, but theseinstances are purely illustrative and it is not intended to excludeother instances when the context so permits.

It is to be understood that R²A¹, (R¹Z¹)_(n) and (R¹Z¹)_(m) may beattached at either a ring carbon or nitrogen atom whereas R³ is attachedat a ring carbon.

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings:

“Patient” includes both human and other mammals.

“Acyl” means an H—CO—or alkyl-CO— group in which the alkyl group is asdescribed herein. Preferred acyls contain a C₁₋₄alkyl. Exemplary acylgroups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyland palmitoyl.

“Acylamino” is an acyl-NH— group wherein acyl is as defined herein.

“Alkoxy” means an alkyl-O— group in which the alkyl group is asdescribed herein. Exemplary alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy and heptoxy.

“Alkoxycarbonyl” means an alkyl-O—CO— group in which the alkyl group isas described herein. Exemplary alkoxycarbonyl groups include methoxy-and ethoxycarbonyl.

“Alkyl” means, unless otherwise specified, an aliphatic hydrocarbongroup which may be straight or branched having about 1 to about 15carbon atoms in the chain, optionally substituted by one or more halogenatoms. Particular alkyl groups have 1 to about 12 carbon atoms in thechain, more particularly from 1 to about 6 carbon atoms. Exemplary alkylgroups for R¹ include methyl, fluoromethyl, difluoromethyl,trifluoromethyl and ethyl. Exemplary alkyl groups for R² include methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl,3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.

“Alkylsulphonyl” means an alkyl-SO₂— group in which the alkyl group isas previously described. Preferred groups are those in which the alkylgroup is C₁₋₄alkyl.

“Alkylsulphinyl” means an alkyl-SO— group in which the alkyl group is aspreviously described. Preferred groups are those in which the alkylgroup is C₁₋₄alkyl.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Exemplary alkylthio groups include methylthio,ethylthio, isopropylthio and heptylthio.

“Aroyl” means an aryl-CO— group in which the aryl group is as describedherein. Exemplary groups include benzoyl and 1- and 2-naphthoyl.

“Aroylamino” is an aroyl-NH— group wherein aroyl is as previouslydefined.

“Aryl” as a group or part of a group denotes an optionally substitutedmonocyclic or multicyclic aromatic carbocyclic moiety of about 6 toabout 10 carbon atoms. When R³ contains an optionally substituted arylgroup this may particularly represent an aromatic carbocyclic moiety ofabout 6 to about 10 carbon atoms such as phenyl or naphthyl optionallysubstituted with one or more aryl group substituents which may be thesame or different, where “aryl group substituent” includes, for example,acyl, acylamino, alkyl, alkoxy, alkoxycarbonyl, alkylthio,alkylsulphinyl, alkylsulphonyl, aroyl, aroylamino, aryl, arylalkyl,arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy,aryloxycarbonyl, arylsulphinyl, arylsulphonyl, carboxy, cyano, halo,heteroaroyl, heteroaryl, heteroarylalkyl, heteroarylamino,heteroaryloxy, hydroxy, hydroxyalkyl, nitro, arylthio, Y⁷Y⁸N—, Y⁷Y⁸NCO—or Y⁷Y⁸NSO₂— (where Y⁷ and Y⁸ are independently hydrogen, alkyl, aryl,and arylalkyl). Preferred aryl group substituents within R³ includeacyl, acylamino, alkoxycarbonyl, alkyl, alkylthio, aroyl, cyano, halo,hydroxy, nitro, Y⁷Y⁸N—, Y⁷Y⁸NCO— and Y⁷Y⁸NSO₂— (where Y⁷ and Y⁸ areindependently hydrogen or alkyl).

When R² contains an optionally substituted aryl group this mayparticularly represent a phenyl group optionally substituted by one ormore substituents selected from the “aryl group substituents” listedabove. Preferred aryl group substituents within R² include halogen,alkoxy, carboxamido, cyano and heteroaryl.

“Arylalkyl” means an aryl-alkyl-group in which the aryl and alkylmoieties are as previously described. Preferred arylalkyl groups containa C₁₋₄alkyl moiety. Exemplary arylalkyl groups include benzyl,2-phenethyl and naphthlenemethyl.

“Arylalkylsulphinyl” means an aryl-alkyl-SO— group in which the aryl andalkyl moieties are as previously described.

“Arylalkylsulphonyl” means an aryl-alkyl-SO— group in which the aryl andalkyl moieties are as previously described.

“Arylalkyloxy” means an arylalkyl-O— group in which the arylalkyl groupsis as previously described. Exemplary arylalkyloxy groups includebenzyloxy and 1- or 2-naphthalenemethoxy.

“Arylalkyloxycarbonyl” means an arylalkyl-O—CO— group in which thearylalkyl groups is as previously described. An exemplaryarylalkyloxycarbonyl group is benzyloxycarbonyl.

“Arylalkylthio” means an arylalkyl-S— group in which the arylalkyl groupis as previously described. An exemplary arylalkylthio group isbenzylthio.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Exemplary aryloxy groups include optionallysubstituted phenoxy and naphthoxy.

“Aryloxycarbonyl” means an aryl-O—CO— group in which the aryl group isas previously described. Exemplary aryloxycarbonyl groups includephenoxycarbonyl and naphthoxycarbonyl.

“Arylsulphinyl” means an aryl-SO— group in which the aryl group is aspreviously described.

“Arylsulphonyl” means an aryl-SO₂— group in which the aryl group is aspreviously described.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Exemplary arylthio groups include phenylthio andnaphthylthio.

“Azaheterocycle” means a heterocycle of about 5 to about 7 ring membersin which one of the ring members is nitrogen and the other ring membersare chosen from carbon, oxygen, sulphur, nitrogen and NR⁵, but excludingcompounds where two O or S atoms are in adjacent positions. Exemplaryazaheterocycles include pyridyl, imidazolyl, pyrrolyl, pyrrolinyl,oxazolyl, thiazolyl, pyrazolyl, pyridazyl, pyrimidinyl, morpholinyl,piperidinyl.

“Azaheteroaryl” means an aromatic carbocyclic moiety of 5 or 6 ringmembers in which one of the ring members is nitrogen and the other ringmembers are chosen from carbon, oxygen, sulphur, or nitrogen. Exemplaryazaheteroaryl rings include isoxazolyl, pyridyl and pyrimidinyl.

“Cycloalkenyl” means a non-aromatic monocyclic ring system containing acarbon-carbon double bond and having about 3 to about 10 carbon atoms.Exemplary monocyclic cycloalkenyl rings include cyclopentenyl,cyclohexenyl and cycloheptenyl.

“Cycloalkenyloxy” means a cycloalkenyl-0-group in which the cycloalkenylmoiety is as previously defined. Exemplary cycloalkyloxy groups includecyclopentenyloxy, cyclohexenyloxy and cycloheptenyloxy.

“Cycloalkyl” means a saturated monocyclic or bicyclic ring system ofabout 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkyl ringsinclude cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

“Cycloalkyloxy” means a cycloalkyl-0-group in which the cycloalkylmoiety is as previously defined. Exemplary cycloalkyloxy groups includecyclopropyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.

“Heteroaroyl” means a heteroaryl-CO— group in which the heteroaryl groupis as described herein. Exemplary groups include pyridylcarbonyl.

“Heteroaryl” as a group or part of a group denotes an optionallysubstituted aromatic monocyclic or multicyclic organic moiety of about 5to about 10 ring members in which one or more of the ring members is/areelement(s) other than carbon, for example nitrogen, oxygen or sulphur.Examples of suitable optionally substituted heteroaryl groups includefuryl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazole, pyrazinyl,pyridazinyl, pyridyl, pyrimidinyl, quinolinyl, 1,3,4-thiadiazolyl,thiazolyl, thienyl, and 1,2,4-triazinyl groups, optionally substitutedby one or more aryl group substituents as defined above. When R² or R³contains an optionally substituted heteroaryl group this mayparticularly represent an optionally substituted “azaheteroaryl” group.Optional substituents for the heteroaryl group within R² or R³ include,for example, halogen atoms and alkyl, aryl, arylalkyl, hydroxy, oxo,hydroxyalkyl, haloalkyl (for example trifluoromethyl), alkoxy,haloalkoxy (for example trifluoromethoxy), aryloxy and arylalkyloxygroups. Preferred heteroaryl groups within R² or R³ include optionallysubstituted pyridyl. Preferred heteroaryl groups represented by R⁶within the groups —C(=Z)NHR⁶ and —C(=Z)CH₂R⁶ are optionally substitutedpyridyl groups, especially wherein the optional substituents are alkylgroups or, more particularly, halogen atoms. Preferred heteroaryl groupsrepresented by R⁶ within the group —C(=Z)R⁶ are optionally substitutedpyridyl groups, especially wherein the optional substituent is anaryloxy group.

“Heteroarylalkyl” means a heteroaryl-alkyl-group in which the heteroaryland alkyl moieties are as previously described. Preferredheteroarylalkyl groups contain a C₁₋₄alkyl moiety. Exemplaryheteroarylalkyl groups include pyridylmethyl.

“Heteroaryloxy” means an heteroaryl-O— group in which the heteroarylgroup is as previously described. Exemplary heteroaryloxy groups includeoptionally substituted pyridyloxy.

“Heteroarylalkoxy” means an heteroarylalkyl-O— group in which theheteroarylalkyl group is as previously described. Exemplaryheteroaryloxy groups include optionally substituted pyridylmethoxy.

“Heterocycloalkyl” means a cycloalkyl group which contains one or moreheteroatoms selected from O, S or NY¹.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyl groups contain C₁₋₄alkyl. Exemplaryhydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

“Y⁷Y⁸N—” means a substituted or unsubstituted amino group, wherein Y⁷and Y⁸ are as previously described. Exemplary groups include amino(H₂N—), methylamino, ethylmethylamino, dimethylamino and diethylamino.

“Y⁷Y⁸NCO—” means a substituted or unsubstituted carbamoyl group, whereinY⁷ and Y⁸ are as previously described. Exemplary groups are carbamoyl(H₂NCO—) and dimethylcarbamoyl (Me₂NCO—).

“Y⁷Y⁸NSO₂—” means a substituted or unsubstituted sulphamoyl group,wherein Y⁷ and Y⁸ are as previously described. Exemplary groups aresulphamoyl (H₂NSO₂—) and dimethylsulphamoyl (Me₂NSO₂—).

“Halo” or “halogen” means fluoro, chloro, bromo, or iodo. Preferred arefluoro or chloro.

“Prodrug” means a compound which is convertible in vivo by metabolicmeans (e.g. by hydrolysis) to a compound of formula (I), includingN-oxides thereof, for example an ester of a compound of formula (I)containing a hydroxy group.

Suitable esters are of many different types, for example acetates,citrates, lactates, tartrates, malonates, oxalates, salicylates,propionates, succinates, fumarates, maleates,methylene-bis-β-hydroxynaphthoates, gentisates, isethionates,di-p-toluoyltartrates, methanesulphonates, ethanesulphonates,benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates andquinates.

An especially useful class of esters may be formed from acid moietiesselected from those described by Bundgaard et. al., J. Med. Chem., 1989,32, page 2503-2507, and include substituted (aminomethyl)-benzoates, forexample dialkylamino-methylbenzoates in which the two alkyl groups maybe joined together and/or interrupted by an oxygen atom or by anoptionally substituted nitrogen atom, e.g. an alkylated nitrogen atom,more especially (morpholino-methyl)benzoates, e.g. 3- or4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates,e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.

Some of the compounds of the present invention are basic, and suchcompounds are useful in the form of the free base or in the form of apharmaceutically acceptable acid addition salt thereof.

Acid addition salts are a more convenient form for use; and in practice,use of the salt form inherently amounts to use of the free base form.The acids which can be used to prepare the acid addition salts includepreferably those which produce, when combined with the free base,pharmaceutically acceptable salts, that is, salts whose anions arenon-toxic to the patient in pharmaceutical doses of the salts, so thatthe beneficial inhibitory effects inherent in the free base are notvitiated by side effects ascribable to the anions. Althoughpharmaceutically acceptable salts of said basic compounds are preferred,all acid addition salts are useful as sources of the free base form evenif the particular salt, per se, is desired only as an intermediateproduct as, for example, when the salt is formed only for purposes ofpurification, and identification, or when it is used as intermediate inpreparing a pharmaceutically acceptable salt by ion exchange procedures.Pharmaceutically acceptable salts within the scope of the inventioninclude those derived from mineral acids and organic acids, and includehydrohalides, e.g. hydrochlorides and hydrobromides, sulphates,phosphates, nitrates, sulphamates, acetates, citrates, lactates,tartrates, malonates, oxalates, salicylates, propionates, succinates,fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates,isethionates, di-p-toluoyltartrates, methane-sulphonates,ethanesulphonates, benzenesulphonates, p-toluenesulphonates,cyclohexylsulphamates and quinates.

Where the compound of the invention is substituted with an acidicmoiety, base addition salts may be formed and are simply a moreconvenient form for use; and in practice, use of the salt forminherently amounts to use of the free acid form. The bases which can beused to prepare the base addition salts include preferably those whichproduce, when combined with the free acid, pharmaceutically acceptablesalts, that is, salts whose cations are non-toxic to the patient inpharmaceutical doses of the salts, so that the beneficial inhibitoryeffects inherent in the free base are not vitiated by side effectsascribable to the cations. Pharmaceutically acceptable salts, includingthose derived from alkali and alkaline earth metal salts, within thescope of the invention include those derived from the following bases:sodium hydride, sodium hydroxide, potassium hydroxide, calciumhydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide,zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylenediamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)aminomethane,tetramethylammonium hydroxide, and the like.

As well as being useful in themselves as active compounds, salts ofcompounds of the invention are useful for the purposes of purificationof the compounds, for example by exploitation of the solubilitydifferences between the salts and the parent compounds, side productsand/or starting materials by techniques well known to those skilled inthe art.

It will be appreciated that compounds of the present invention maycontain asymmetric centres. These asymmetric centres may independentlybe in either the R or S configuration. It will be apparent to thoseskilled in the art that certain compounds of the invention may alsoexhibit geometrical isomerism. It is to be understood that the presentinvention includes individual geometrical isomers and stereoisomers andmixtures thereof, including racemic mixtures, of compounds of formula(I) hereinabove. Such isomers can be separated from their mixtures, bythe application or adaptation of known methods, for examplechromatographic techniques and recrystallization techniques, or they areseparately prepared from the appropriate isomers of their intermediates.Additionally, in situations where tautomers of the compounds of formula(I) are possible, the present invention is intended to include alltautomeric forms of the compounds.

With reference to formula (I) above, the following are particular andpreferred groupings:

R¹ preferably represents a C₁₋₄alkyl group optionally substituted by oneor more halogen (e.g. chlorine or fluorine) atoms. R¹ more preferablyrepresents methyl or difluoromethyl.

R² may particularly represent C₁₋₇alkyl (for example methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl).

R² may also particularly represent C₁₋₄alkoxy (for example methoxy).

R² may also particularly represent C₃₋₇cycloalkyl (for examplecyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl).

R² may also particularly represent aryl (for example optionallysubstituted phenyl or naphthyl).

R² may also particularly represent aryloxy (for example optionallysubstituted phenoxy).

R² may also particularly represent heteroaryl (for example optionallysubstituted thienyl, pyridyl, furanyl).

R² may also particularly represent heterocycloalkyl (for exampletetrahydrofuranyl, tetrahydropyranyl).

R² may also particularly represent arylalkylsulphonyl (for example4-methylphenylsulphonyl and 4-methoxyphenylsulphonyl) when the groupR²A¹— is attached to a ring nitrogen atom.

It is to be understood that the aforementioned heteroaryl andheterocycloalkyl moieties represented by R² when containing at least onenitrogen atom may be presented as the corresponding N-oxides.

R³ may particularly represent —OCH₂R⁶, —C(=Z)—N(R⁷)R⁶, preferablywherein R⁷ represents a hydrogen atom, or —C(=Z)—CHR¹²R⁶ especiallywhere R¹² is hydrogen.

Within such groups R⁶ may preferably represent substituted phenyl,especially a phenyl group substituted on one or both, more preferably onboth, of the positions adjacent to a position of attachment of R⁶ to therest of the molecule. It is also preferred that the phenyl substituentis alkyl, especially methyl, or halo, especially chloro or fluoro.Within such groups R⁶ may also preferably represent substitutedazaheteroaryl, where the azaheteroaryl group is preferably substitutedon one or both, more preferably on both, of the positions adjacent to aposition of attachment of R⁶ to the rest of the molecule. It is alsopreferred that the heteroaryl substituent is alkyl, especially methyl,or halo, especially chloro or fluoro.

R³ may also particularly represent —C(=Z)—R⁶ wherein R⁶ is preferablyazaheteroaryl (e.g. pyridyl), particularly when substituted by aryloxy(e.g. 3-chlorophenoxy).

R³ may also particularly represent —CR⁸═C(R⁹)(CH₂)_(p)—R⁶ where R⁸ ispreferably CH₃ or more preferably hydrogen, R⁹ is preferably hydrogen,CN or CH₃ and p is zero, 1 or 2, especially zero and R⁶ is as definedabove.

R³ may also particularly represent —C(R¹⁰)═C(R¹¹)R¹² where R¹⁰ and R¹¹are each preferably CH₂R⁶ or especially R⁶ (where R⁶ is as definedabove), and R¹² is hydrogen.

R³ may also particularly represent —C(R¹³)(R¹⁰)C(R¹¹)(R¹⁴)R¹² where R¹⁰and R¹¹ are each preferably CH₂R⁶ or especially R⁶ (where R⁶ is asdefined above), R¹³ is preferably hydrogen or hydroxy, R¹² and R¹⁴ arepreferably methyl or more especially hydrogen.

R³ may also particularly represent —C(R⁸)(R¹⁵)CH(R⁹)(CH₂)_(p)—R⁶ whereR⁸ is preferably CH₃ or more preferably hydrogen, R⁹ and is preferablyhydrogen, CN or CH₃, more preferably hydrogen, p is zero, 1 or 2,especially zero, R¹⁵ is preferably hydrogen and R⁶ is as defined above.

R³ may also particularly represent —R⁶ where R⁶ is as defined above.

R³ may also particularly represent —N(R¹⁶)C(=Z)R⁶ where R¹⁶ is hydrogenand R⁶ is as defined above.

R³ may also particularly represent —C(R¹⁷)═N—OC(═O)R¹⁸ where R¹⁷ isC₁₋₄alkyl and R¹⁸ is amino.

R³ may also particularly represent —C(═O)—N(R¹⁹)OR²⁰ where R¹⁹ isC₁₋₄alkyl or aryl and R²⁰ is C₁₋₄alkyl or arylalkyl.

R³ may also particularly represent —C≡C—R⁶, —CH₂—NHR⁶, —CH₂—SOR⁶,—CH₂—SO₂R⁶, —CF₂—OR⁶, —NH—CH₂R⁶, —SO—CH₂R⁶, —SO₂—CH₂R⁶, —O—CF₂R⁶,—N═N—R⁶, —NH—SO₂R⁶, — —NH—CO—OR⁶, —O—CO—NHR⁶, —NH—CO—NHR⁶ or—CH₂—CO—CH₂R⁶ where R⁶ is as defined above.

R³ may also particularly represent —SO₂—NR²¹R²² where R²¹ and R²² are asdefined above.

R³ may also particularly represent —CH₂—C(=Z)—R⁶, —C(=Z)—C(=Z)R⁶,—CH₂-ZR⁶, -Z-CH₂R⁶, CZ-CZ-NHR⁶ or —O—C(=Z)R⁶ where Z and R⁶ are asdefined above.

R³ may also particularly represent —CX¹═CX²R⁶ where X¹, X² and R⁶ are asdefined above.

R³ may also particularly represent —C(═NOR²⁴)—(CH₂)_(q)R⁶ where R²⁴, qand R⁶ are as defined above.

R³ may also particularly represent —CH₂—CO—NH(CH₂)_(q)R⁶ or—CH₂—NH—CO(CH₂)_(q)R⁶ where q and R⁶ are as defined above.

R³ may also particularly represent —C(═NR²⁵)—NH(CH₂)_(q)R⁶ where R²⁵, qand R⁶ are as defined above.

R³ may also particularly represent —C(X³)═N—(CH₂)_(q)R⁶ or where X³, qand R⁶ are as defined above.

R³ may also particularly represent —CH(X⁴)—CH₂R⁶ where X⁴ and R⁶ are asdefined above.

R³ may also particularly represent

where R³⁰ and R³² are hydrogen and R³¹ is —CO₂H or —CONHOH.

R³ may also particularly represent

R³ may also particularly represent

R³ may also particularly represent

R³ may also particularly represent

where R³³ is CN, s is zero and Z³ is an oxygen atom.

R³ may also particularly represent

where R³³ is CN, s is zero and Z³ is an oxygen atom.

R³ may also particularly represent

where R³³ is CN, s is zero, R³⁵ is hydrogen and R³⁶ is CO₂H.

R³ may also particularly represent

where R³³ is CN, s is zero and

R⁵ is hydrogen or C₁₋₄alkyl, especially methyl.

R³ may also particularly represent

where R³³ is CN, s is zero and

R⁵ is hydrogen or C₁₋₄alkyl, especially methyl.

R³ may also particularly represent

where W is NR³⁹ [where R³⁹ is C₁₋₄alkyl, especially methyl] and R³⁷ isCONHR⁵ [where R⁵ is heteroarylalkyl, especially pyridylmethyl].

R³ may also particularly represent

where W is CH₂ and R³⁷ is hydrogen.

R³ may also particularly represent

where W is CH₂ and R³⁸ is hydroxymethyl.

R³ may also particularly represent

where W is CH₂ and R³⁸ is carboxy.

R³ may also particularly represent

where R³⁷ is hydrogen.

R³ may also particularly represent

where R³⁷ and R³⁹ are alkoxycarbonyl.

R³ may also particularly represent

where R³⁷ is hydroxy and R³⁹ is hydrogen.

R³ may also particularly represent

where R⁴⁰ is hydrogen, R⁴¹ is C₁₋₄alkoxycarbonyl, especially methyl, R⁴²is C₁₋₄alkyl, especially methyl, and R³⁸ is C₁₋₄acyl, especially acetyl.

R³ may also particularly represent

where Y is defined above.

The moiety A¹ may particularly represent a direct bond or a straight- orbranched-chain alkylene linkage containing from 1 to 6 carbon atoms,optionally substituted by alkoxy.

Z¹ may particularly represents an oxygen atom.

Z¹ may also particularly represents a direct bond.

The moiety R³ is preferably —C(═O)—NHR⁶, —C(═O)—CH₂R⁶ or —OCH₂R⁶ whereinR⁶ represents an optionally substituted azaheteroaryl group, especiallya pyridyl or isoxazolyl, substituted (by one or two methyl groups orhalogen, e.g. chlorine atoms) on one or both, more preferably both, ofthe positions adjacent to the position of attachment of R⁶ to the restof the molecule. Particular examples of R⁶-include a 3,5-dimethyl- or3,5-dihalopyrid-4-yl moiety (more especially a 3,5-dimethylpyrid-4-ylmoiety) or 3,5-dimethyl-isoxazol-4-yl.

It is to be understood that the aforementioned heteroaryl moietiespresent within R³ when containing at least one nitrogen atom may bepresented as the corresponding N-oxides, and such N-oxides are alsopreferred. Thus, R³ may preferably contain a 3,5-dialkyl- or3,5-dihalo-1-oxido-4-pyridinio group, such as a 3,5-dimethyl- or3,5-dichloro-1-oxido-4-pyridinio group.

In compounds of formula (I) ring

may particularly represent a 5-membered azaheterocycle containing atleast one nitrogen atom, and ring

may particularly represent a 6-membered azaheteroaryl or preferably abenzene ring. Such compounds in which n is zero and m is 1 arepreferred.

The bicycle

may particularly represent

where Q¹ is a CH or CX⁵ linkage (where X⁵ is halogen), or a nitrogenatom, or N⁺—O⁻, especially a CH linkage, and the moiety

especially where R⁵ represents a hydrogen atom or a methyl group, moreespecially where R⁵ is hydrogen. Preferred compounds have R²A¹ attachedto position 2 of the benzimidazole ring.

It will be appreciated that compounds of formula (I) in which thebicycle

where the moiety

where R⁵ represents a hydrogen atom, are tautomers.

The bicycle

may also particularly represent

especially where R²A¹ is attached to the ring nitrogen atom.

The bicycle

may also particularly represent

especially where R²A¹ is attached to the ring nitrogen atom.

The bicycle

may also particularly represent

(wherein Z is as hereinbefore defined, especially an oxygen atom)especially where R²A¹ is attached to position 2 of the benzoxazole ring.

The bicycle

may also particularly represent

especially where R²A¹ is attached to the ring nitrogen atom.

The bicycle

may also particularly represent

especially where R²A¹ is attached to position 2 of the quinoline ring.

It is to be understood that this invention covers all appropriatecombinations of the particular and preferred groupings referred toherein.

A further particular group of compounds of the present invention arecompounds of formula (Ia):

wherein R¹, R², R³, A¹,

Z¹ and Q¹ are as defined previously, and N-oxides thereof, and theirprodrugs, and pharmaceutically acceptable salts and solvates (e.g.hydrates) of the compounds of formula (Ia) and N-oxides thereof, andtheir prodrugs.

Compounds of formula (Ia) in which R¹ represents C₁₋₄alkyl optionallysubstituted by one or more halogen atoms (especially methyl ordifluoromethyl) are preferred.

Compounds of formula (Ia) in which R² represents a straight- orbranched-chain C₁₋₄alkyl group (e.g. isopropyl), or cycloalkyl (e.g.cyclopropyl), alkoxy (e.g. methoxy), aryl, aryloxy or heteroaryl (e.g.pyridyl) are preferred.

Compounds of formula (Ia) in which R³ represents —C(═O)—NHR⁶,—C(═O)—CH₂R⁶ or —O—CH₂R⁶ where R⁶ represents

a disubstituted azaheteroaryl group, or an N-oxide thereof, moreparticularly a dialkyl- or dihalo-azaheteroaryl group or an N-oxidethereof, are preferred. Azaheteroaryl groups substituted on both of thepositions adjacent to the position of attachment of R⁶ to the rest ofthe molecule, for example 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl-or 3,5-dichloro-pyrid-4-yl or an N-oxide thereof, are most preferred.

Compounds of formula (Ia) in which A¹ represents a direct bond are apreferred group of compounds.

Compounds of formula (Ia) in which A¹ represents a straight or branchedchain alkylene linkage containing from 1 to 6 carbon atoms, for examplea methylene, ethylene, propylene, methylmethylene, or butylmethylenelinkage, (especially methylene) are also a preferred group of compounds.

Compounds of formula (Ia) in which A¹ represents a straight or branchedchain alkylene linkage containing from 1 to 6 carbon atoms which issubstituted by alkoxy, for example a methoxymethylene ormethoxypropylmethylene, are a further preferred group of compounds.

Compounds of formula (Ia) in which the moiety

where R⁵ represents a hydrogen atom or a methyl group (especially ahydrogen atom) are preferred.

Compounds of formula (Ia) in which Q¹ is a CH linkage are preferred.

Compounds of formula (Ia) in which Z¹ is an oxygen atom are preferred.

A preferred group of compounds of the invention are compounds of formula(Ia) in which: R¹ is methyl or difluoromethyl; R² is C₁₋₄alkyl (e.g.isopropyl), C₃₋₆cycloalkyl (e.g. cyclopropyl), C₁₋₄alkoxy (e.g.methoxy), aryl, aryloxy or azaheteroaryl; R³ represents —C(═O)—NHR⁶,—C(═O)—CH₂R⁶ or —O—CH₂R⁶ where R⁶ is a dimethyl- or dihalo-azaheteroaryl(e.g. 3,5-dimethyl- isoxazol-4-yl, or 3,5-dimethyl- or3,5-dichloro-pyrid-4-yl, or an N-oxide thereof); A¹ is a direct bond ora methylene linkage;

Q¹ is a CH linkage and Z¹ is an oxygen atom, and N-oxides thereof, andtheir prodrugs, and pharmaceutically acceptable salts and solvates (e.g.hydrates) of the compounds of formula (Ia) and N-oxides thereof, andtheir prodrugs.

A further particular group of compounds of the present invention arecompounds of formula (Ib):

wherein R¹, R², R³, A¹ and Z¹ are as defined previously, and Qrepresents a CH linkage or a nitrogen atom, and N-oxides thereof, andtheir prodrugs, and pharmaceutically acceptable salts and solvates (e.g.hydrates) of the compounds of formula (Ib) and N-oxides thereof, andtheir prodrugs.

Compounds of formula (Ib) in which R¹ represents methyl is preferred.

Compounds of formula (Ib) in which R² represents a straight- orbranched-chain C₄₋₉alkyl group (e.g. heptyl), a cycloalkyl group (e.g.cyclopentyl, cyclohexyl), an aryl (e.g. optionally substituted phenyl),a heteroaryl (e.g. optionally substituted thienyl) or heterocycloalkyl(e.g. tetrahydofuranyl, tetrahydropyranylmethyl) are preferred.Compounds of formula (Ib) in which R³ represents —C(═O)—NHR⁶,—C(═O)—CH₂R⁶ or —O—CH₂R⁶ where R⁶ represents

a disubstituted azaheteroaryl group, or a N-oxide thereof, moreparticularly a dialkyl- or dihalo-azaheteroaryl group or an N-oxidethereof, are preferred. Azaheteroaryl groups substituted on both of thepositions adjacent to the position of attachment of R⁶ to the rest ofthe molecule, for example 3,5-dimethyl-isoxazolyl, or 3,5-dimethyl- or3,5-chloro-pyridyl or an N-oxide thereof, are most preferred.

Compounds of formula (Ib) in which A¹ represents a direct bond are apreferred group of compounds.

Compounds of formula (Ib) in which A¹ represents a straight or branchedchain alkylene linkage containing from 1 to 6 carbon atoms, for examplea methylene, ethylene, propylene, methylmethylene, butylmethylenelinkage, (especially methylene) are also a preferred group of compounds.

Compounds of formula (Ib) in which Q represents a CH linkage or anitrogen atom are preferred.

Compounds of formula (Ib) in which Z¹ represents a direct bond arepreferred.

A preferred group of compounds of the invention are compounds of formula(Ib) in which: R¹ is hydrogen or methyl; R² is C₄₋₉alkyl (e.g. heptyl),C₃₋₇cycloalkyl (e.g. cyclopentyl, cyclohexyl), aryl, heteroaryl (e.g.optionally substituted thienyl), heterocycloalkyl (e.g.tetrahydofuranyl, tetrahydropyranylmethyl); R³ represents —C(═O)—NHR⁶,—C(═O)—CH₂R⁶ or —O—CH₂R⁶ where R⁶ is a dimethyl- or dihalo-azaheteroaryl(e.g. 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or3,5-dichloro-pyrid-4-yl, or an N-oxide thereof); A¹ is a direct bond ora methylene linkage and Z¹ is a direct bond and Q is a CH linkage or anitrogen atom, and N-oxides thereof, and their prodrugs, andpharmaceutically acceptable salts and solvates (e.g. hydrates) of thecompounds of formula (Ib) and N-oxides thereof, and their prodrugs.

A further particular group of compounds of the present invention arecompounds of formula (Ic):

wherein R¹, R², R³, A¹, Q¹, Z and Z¹ are as defined previously, andN-oxides thereof, and their prodrugs, and pharmaceutically acceptablesalts and solvates (e.g. hydrates) of the compounds of formula (Ic) andN-oxides thereof, and their prodrugs.

Compounds of formula (Ic) in which R¹ represents methyl ordifluoromethyl are preferred.

Compounds of formula (Ic) in which R² represents a straight- orbranched-chain C₁₋₄alkyl group (e.g. isopropyl), a cycloalkyl group(e.g. cyclopropyl), alkoxy (e.g. methoxy), aryl, aryloxy, heteroaryl(e.g. pyridyl) are preferred.

Compounds of formula (Ic) in which R³ represents —C(═O)—NHR⁶,—C(═O)—CH₂R⁶ or —O—CH₂R⁶ where R⁶ represents

a disubstituted azaheteroaryl group, or a N-oxide thereof, moreparticularly a dialkyl- or dihalo-azaheteroaryl group or an N-oxidethereof, are preferred. Azaheteroaryl groups substituted on both of thepositions adjacent to the position of attachment of R⁶ to the rest ofthe molecule, for example 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl-or 3,5-dichloro-pyrid-4-yl or an N-oxide thereof, are most preferred.

Compounds of formula (Ic) in which A¹ represents a direct bond are apreferred group of compounds.

Compounds of formula (Ic) in which A¹ represents a straight or branchedchain alkylene linkage containing from 1 to 6 carbon atoms, for examplea methylene, ethylene, propylene, methylmethylene, or butylmethylenelinkage, (especially methylene) are also a preferred group of compounds.

Compounds of formula (Ic) in which A¹ represents a straight or branchedchain alkylene linkage containing from 1 to 6 carbon atoms which issubstituted by alkoxy, for example a methoxymethylene ormethoxypropylmethylene, are a further preferred group of compounds.

Compounds of formula (Ic) in which Q¹ is a CH linkage are preferred.

Compounds of formula (Ic) in which Z is an oxygen atom are preferred.

Compounds of formula (Ic) in which Z¹ is an oxygen atom are preferred.

A preferred group of compounds of the invention are compounds of formula(Ic) in which: R¹ is methyl or difluoromethyl; R² is C₁₋₄alkyl (e.g.isopropyl), C₃₋₆cycloalkyl (e.g. cyclopropyl), C₁₋₄alkoxy (e.g.methoxy), aryl, aryloxy or azaheteroaryl; R³ represents —C(═O)—NHR⁶,—C(═O)—CH₂R⁶ or —O—CH₂R⁶ where R⁶ is a dimethyl- or dihalo-azaheteroaryl(e.g. 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or3,5-dichloro-pyrid-4-yl, or an N-oxide thereof); A¹ is a direct bond ora methylene linkage; Q¹ is a CH linkage; and Z and Z¹ are both oxygenatoms, and N-oxides thereof, and their prodrugs, and pharmaceuticallyacceptable salts and solvates (e.g. hydrates) of the compounds offormula (Ic) and N-oxides thereof, and their prodrugs.

A further particular group of compounds of the present invention arecompounds of formula (Id):

wherein R¹, R², R³, A¹, Q¹, Z and Z¹ are as defined previously, andN-oxides thereof, and their prodrugs, and pharmaceutically acceptablesalts and solvates (e.g. hydrates) of the compounds of formula (Id) andN-oxides thereof, and their prodrugs.

Compounds of formula (Id) in which R¹ represents methyl ordifluoromethyl are preferred.

Compounds of formula (Id) in which R² represents a straight- orbranched-chain C₁₋₄alkyl group (e.g. isopropyl), a cycloalkyl group(e.g. cyclopropyl), alkoxy (e.g. methoxy), aryl, aryloxy, heteroaryl(e.g. pyridyl) are preferred.

Compounds of formula (Id) in which R³ represents —C(═O)—NHR⁶,—C(═O)—CH₂R⁶ or —O—CH₂R⁶ where R⁶ represents

a disubstituted azaheteroaryl group, or a N-oxide thereof, moreparticularly a dialkyl- or dihalo-azaheteroaryl group or an N-oxidethereof, are preferred. Azaheteroaryl groups substituted on both of thepositions adjacent to the position of attachment of R⁶ to the rest ofthe molecule, for example 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl-or 3,5-dichloro-pyrid-4-yl or an N-oxide thereof, are most preferred.

Compounds of formula (Id) in which A¹ represents a direct bond are apreferred group of compounds.

Compounds of formula (Id) in which A¹ represents a straight or branchedchain alkylene linkage containing from 1 to 6 carbon atoms, for examplea methylene, ethylene, propylene, methylmethylene, or butylmethylenelinkage, (especially methylene) are also a preferred group of compounds.

Compounds of formula (Id) in which A¹ represents a straight or branchedchain alkylene linkage containing from 1 to 6 carbon atoms which issubstituted by alkoxy, for example a methoxymethylene ormethoxypropylmethylene, are a further preferred group of compounds.

Compounds of formula (Id) in which Q¹ is a CH linkage are preferred.

Compounds of formula (Id) in which Z is an oxygen atom are preferred.

Compounds of formula (Id) in which Z¹ is an oxygen atom are preferred.

A preferred group of compounds of the invention are compounds of formula(Id) in which: R¹ is methyl or difluoromethyl; R² is C₁₋₄alkyl (e.g.isopropyl), C₃₋₆cycloalkyl (e.g. cyclopropyl), C₁₋₄alkoxy (e.g.methoxy), aryl, aryloxy or azaheteroaryl; R³ represents —C(═O)—NHR⁶,—C(═O)—CH₂R⁶ or —O—CH₂R⁶ where R⁶ is a dimethyl- or dihalo-azaheteroaryl(e.g. 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or3,5-dichloro-pyrid-4-yl, or an N-oxide thereof); A¹ is a direct bond ora methylene linkage; Q¹ is a CH linkage; and Z and Z¹ are both oxygenatoms, and N-oxides thereof, and their prodrugs, and pharmaceuticallyacceptable salts and solvates (e.g. hydrates) of the compounds offormula (Id) and N-oxides thereof, and their prodrugs.

A further particular group of compounds of the present invention arecompounds of formula (Ie):

wherein R¹, R², R³, A¹ and Z¹ are as defined previously, and N-oxidesthereof, and their prodrugs, and pharmaceutically acceptable salts andsolvates (e.g. hydrates) of the compounds of formula (Ie) and N-oxidesthereof, and their prodrugs.

Compounds of formula (Ie) in which R¹ represents methyl are preferred.

Compounds of formula (Ie) in which R² represents a straight- orbranched-chain C₄₋₉alkyl group (e.g. heptyl), a cycloalkyl group (e.g.cyclopentyl, cyclohexyl), an aryl (e.g. optionally substituted phenyl),a heteroaryl (e.g. optionally substituted thienyl) or heterocycloalkyl(e.g. tetrahydofuranyl, tetrahydropyranylmethyl) are preferred.

Compounds of formula (Ie) in which R³ represents —C(═O)—NHR⁶,—C(═O)—CH₂R⁶ or —O—CH₂R⁶ where R⁶ represents

a disubstituted azaheteroaryl group, or a N-oxide thereof, moreparticularly a dialkyl- or dihalo-azaheteroaryl group or an N-oxidethereof, are preferred. Azaheteroaryl groups substituted on both of thepositions adjacent to the position of attachment of R⁶ to the rest ofthe molecule, for example 3,5-dimethyl-isoxazolyl, or 3,5-dimethyl- or3,5-chloro-pyridyl or an N-oxide thereof, are most preferred.

Compounds of formula (Ie) in which A¹ represents a direct bond are apreferred group of compounds.

Compounds of formula (Ie) in which A¹ represents a straight or branchedchain alkylene linkage containing from 1 to 6 carbon atoms, for examplea methylene, ethylene, propylene, methylmethylene, butylmethylenelinkage, (especially methylene) are also a preferred group of compounds.

Compounds of formula (Ie) in which Z¹ represents a direct bond arepreferred.

A preferred group of compounds of the invention are compounds of formula(Ie) in which: R¹ is hydrogen or methyl; R² is C₄₋₉alkyl (e.g. heptyl),C₃₋₇cycloalkyl (e.g. cyclopentyl, cyclohexyl), aryl, heteroaryl(e.g.optionally substituted thienyl) or heterocycloalkyl (e.g.tetrahydofuranyl, tetrahydropyranylmethyl); R³ represents —C(═O)—NHR⁶,—C(═O)—CH₂R⁶ or —O—CH₂R⁶ where R⁶ is a dimethyl- or dihalo-azaheteroaryl(e.g. 3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or3,5-dichloro-pyrid-4-yl, or an N-oxide thereof); A¹ is a direct bond ora methylene linkage and Z¹ is a direct bond, and N-oxides thereof, andtheir prodrugs, and pharmaceutically acceptable salts and solvates (e.g.hydrates) of the compounds of formula (Ie) and N-oxides thereof, andtheir prodrugs.

A further particular group of compounds of the present invention arecompounds of formula (If):

wherein R¹, R², R³, A¹ and Z¹ are as defined previously, and N-oxidesthereof, and their prodrugs, and pharmaceutically acceptable salts andsolvates (e.g. hydrates) of the compounds of formula (If) and N-oxidesthereof, and their prodrugs.

Compounds of formula (If) in which R¹ represents methyl ordifluoromethyl are preferred.

Compounds of formula (If) in which R² represents a straight- orbranched-chain C₁₋₄alkyl group (e.g. propyl), a cycloalkyl group (e.g.cyclopropyl), aryl, heteroaryl, or heterocycloalkyl are preferred.

Compounds of formula (If) in which R³ represents —C(═O)—NHR⁶,—C(═O)—CH₂R⁶ or —O—CH₂R⁶ where R⁶ represents

a disubstituted azaheteroaryl group, or a N-oxide thereof, moreparticularly a dialkyl- or dihalo-azaheteroaryl group or an N-oxidethereof, are preferred. Azaheteroaryl groups substituted on both of thepositions adjacent to the position of attachment of R⁶ to the rest ofthe molecule, for example 3,5-dimethyl-isoxazolyl, or 3,5-dimethyl- or3,5-chloro-pyridyl or an N-oxide thereof, are most preferred.

Compounds of formula (If) in which A¹ represents a direct bond are apreferred group of compounds.

Compounds of formula (If) in which A¹ represents a straight or branchedchain alkylene linkage containing from 1 to 6 carbon atoms, for examplea methylene, ethylene, propylene, methylmethylene, butylmethylenelinkage, (especially methylene) are also a preferred group of compounds.

Compounds of formula (If) in which Z¹ represents an oxygen atom arepreferred.

A preferred group of compounds of the invention are compounds of formula(If) in which: R¹ is hydrogen or methyl; R² is C₁₋₄alkyl (e.g. propyl),C₃₋₇cycloalkyl (e.g. cyclopentyl, cyclohexyl), aryl, heteroaryl orheterocycloalkyl; R³ represents —C(═O)—NHR⁶, —C(═O)—CH₂R⁶ or —O—CH₂R⁶where R⁶ is dimethyl- or dihalo-azaheteroaryl (e.g.3,5-dimethyl-isoxazol-4-yl, or 3,5-dimethyl- or 3,5-dichloro-pyrid-4-yl,or an N-oxide thereof); A¹ is a direct bond or a methylene linkage andZ¹ is an oxygen atom, and N-oxides thereof, and their prodrugs, andpharmaceutically acceptable salts and solvates (e.g. hydrates) of thecompounds of formula (If) and N-oxides thereof, and their prodrugs.

A further preferred group of compounds of the invention are compounds offormula (Ig):

wherein

-   -   R¹ represents hydrogen, or a straight- or branched-chain alkyl        group of 1 to about 4 carbon atoms, optionally substituted by        one or more halogen atoms;    -   R² represents hydrogen, alkoxy, alkyl, alkylsulphinyl,        alkylsulphonyl, alkylthio, aryl, arylalkyloxy,        arylalkylsulphinyl, arylalkylsulphonyl, arylalkylthio, aryloxy,        arylsulphinyl, arylsulphonyl, arylthio, cycloalkenyl,        cycloalkenyloxy, cycloalkyl, cycloalkyloxy, heteroaryl,        heteroarylalkyloxy, heteroaryloxy, hydroxy, —SO₂NR⁴R⁵,        —NR⁴SO₂R⁵, —NR⁴R⁵, —C(═O)R⁵, —C(═O)C(═O)R⁵, —C(═O)NR⁴R⁵,        —C(═O)OR⁵, —O(C═O)NR⁴R⁵, or —NR⁴C(═O)R⁵ where R⁴ and R⁵, which        may be the same or different, each represent a hydrogen atom, or        an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group;    -   R³ represents a group selected from:    -   (i) —C(=Z)—N(R^(a))R⁶    -   (ii) —C(=Z)—CH₂R⁶    -   (iii) —C(=Z)—R⁶    -   (iv) —CR⁷═C(R⁸)(CH₂)_(n)—R⁶    -   (v) —C(R⁹)═C(R¹⁰)R¹¹    -   (vi) —C(R¹²)(R⁹)C(R¹⁰)(R¹³)R¹¹    -   (vii) —C(R⁷)(R¹⁴)CH(R⁸)(CH₂)_(n)—R⁶    -   (viii) —R⁶    -   (ix) —N(R¹⁵)C(=Z)R⁶    -   (x) —C(CH₃)═N—OC(=0)NH₂    -   (xi) —C(═O)—N(CH₃)OCH₃    -   (xii) —C≡C—R⁶    -   (xiii) —CH₂—C(=Z)—R⁶    -   (xiv) —C(=Z)—C(=Z)R⁶    -   (xv) —CH₂—NHR⁶    -   (xvi) —CH₂-ZR⁶    -   (xvii) —CF₂—OR⁶    -   (xviii) —NH—CH₂R⁶    -   (xix) -Z-CH₂R⁶    -   (xx) —SO—CH₂R⁶    -   (xxi) —SO₂—CH₂R⁶    -   (xxii) —O—CF₂R⁶    -   (xxiii) —O—C(=Z)R⁶    -   (xxiv) —N═N—R⁶    -   (xxv) —NH—SO₂R⁶    -   (xxvi) —SO₂—NHR⁶    -   (xxvii) —CZ-CZ-NHR⁶    -   (xxviii) —NH—CO—OR⁶    -   (xxix) —O—CO—NHR⁶    -   (xxx) —NH—CO—NHR⁶    -   (xxxi) —R¹⁶    -   (xxxii) —CX²═CX³R⁶        [where R^(a) is a hydrogen atom or alkyl, hydroxy or amino;

-   R⁶ is aryl or heteroaryl;

-   R⁷ and R⁸, which may be the same or different, is each a hydrogen    atom or alkyl, —CO₂R¹⁷ (where R¹⁷ is hydrogen or an alkyl, arylalkyl    or aryl group), —C(=Z)NR¹⁸R¹⁹ (where R¹⁸ and R¹⁹ may be the same or    different and each is as described for R¹⁷), —CN or —CH₂CN;

-   n is zero or an integer 1, 2 or 3;

-   R⁹ and R¹⁰, which may be the same or different, is each a group    —(CH₂)_(n)R⁶;

-   R¹¹ is a hydrogen atom or alkyl;

-   R¹² is a hydrogen or halogen atom or an —OR²⁰ group (where R²⁰ is a    hydrogen atom or an alkyl, alkenyl, alkoxyalkyl or acyl group, or    carboxamido or thiocarboxamido group);

-   R¹³ represents hydrogen or alkyl;

-   R¹⁴ is hydrogen or hydroxyl;

-   R¹⁵ is hydrogen, alkyl, amino, aryl, arylalkyl, or hydroxy;

-   where W is (CH₂)_(m) or NR²²;

-   R²¹ and R²² which may be the same or different is each a hydrogen    atom, alkyl, acyl, arylalkyl, —CO₂R¹⁷, heteroarylalkyl, aryl, or    heteroaryl;

-   m is 1 to 4;

-   X² and X³ which may be the same or different is each a hydrogen or    fluorine atom;

-   Z represents an oxygen or sulphur atom];    -   A¹ represents a direct bond, or a straight or branched        C₁₋₆alkylene chain optionally substituted by hydroxyl, alkoxy,        oxo, cycloalkyl, aryl or heteroaryl.        where R²³ represents a hydrogen atom or a C₁₋₄straight- or        branched-chain alkyl, aryl, arylC₁₋₄alkyl, heteroaryl or        heteroarylC₁₋₄alkyl group;

Z¹ represents a direct bond, or an oxygen or sulphur atom, or NH;

Q¹ represents a CH or CX¹ linkage or a nitrogen atom; and

X¹ represents a halogen atom;

and N-oxides thereof, and their prodrugs, pharmaceutically acceptablesalts, and solvates (e.g. hydrates), thereof.

Particular compounds of the invention are selected from the following:

-   N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenyl-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenethyl-3H-benzimidazole-4-carboxamide;-   2-benzyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   (RS)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxamide;-   (R)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxamide;-   (S)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxybenzyl)-3H-benzimidazole-4-carboxamide;-   (RS)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   (R)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   (S)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   (RS)—N-(3,5-dichloro-4-pyridyl)-2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   (R)—N-(3,5-dichloro-4-pyridyl)-2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   (S)—N-(3,5-dichloro-4-pyridyl)-2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   (RS)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-phenylpropyl)-3H-benzimidazole-4-carboxamide;-   (R)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-phenylpropyl)-3H-benzimidazole-4-carboxamide;-   (S)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-phenylpropyl)-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxyphenoxymethyl)-3H-benzimidazole-4-carboxamide;-   (RS)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxamide;-   (R)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxamide;-   (S)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxamide;-   2-(4-bromobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   (RS)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[3-methoxy-1-phenylpropyl]-3H-benzimidazole-4-carboxamide;-   (R)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[3-methoxy-1-phenylpropyl]-3H-benzimidazole-4-carboxamide;-   (S)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[3-methoxy-1-phenylpropyl]-3H-benzimidazole-4-carboxamide;-   2-(4-cyanobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[4-(3-pyridyl)benzyl]-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-methoxybenzyl)-3H-benzimidazole-4-carboxamide;-   (RS)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(methoxy-phenyl)methyl-3H-benzimidazole-4-carboxamide;-   (R)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxy-phenyl)methyl-3H-benzimidazole-4-carboxamide;-   (S)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxy-phenyl)methyl-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-methoxyphenoxy)methyl-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(3-pyridyl)-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-2-isopropyl-7-methoxy-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methyl-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenoxymethyl-3H-benzimidazole-4-carboxamide;-   2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   2-benzyl-N-(3,5-dichloro-4-pyridyl)-3H-benzimidazole-4-carboxamide;-   2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-1-methyl-benzimidazole-4-carboxamide;-   2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3-methyl-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-2,7-dimethoxy-3H-benzimidazole-4-carboxamide;-   2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   2-cyclopropyl-N-(2,6-difluorophenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   2-cyclopropyl-N-(2,6-dibromophenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   2-cyclopropyl-N-(2,6-dimethylphenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   2-cyclopropyl-N-(2,4,6-trifluorophenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   2-cyclopropyl-N-(2,6-dichlorophenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   2-cyclopropyl-N-(3,5-dimethyl-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   2-cyclopropyl-N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;-   2-cyclopropyl-N-(4-carboxy-2,6-dimethylphenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   N-(4-carboxy-2,6-dimethylphenyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;-   N-(3-chloro-4-pyridyl)-7-methoxy-2-propyl-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-8-methoxy-2-n-propyl    quinoline-5-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide;-   1-butyloxycarbonyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-1H-indole-6-carboxamide;-   1-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-3-methyl-N-(4-pyridyl)-1H-indole-6-carboxamide;-   1-benzyl-N-(4-hydroxyphenyl)-3-methyl-1H-indole-6-carboxamide;-   1-(2-cyclohexyl)ethyl-3-methyl-N-(4-pyrimidinyl)-1H-indole-6-carboxamide;-   1-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-N-(3,5-dimethyl-[1,2,4]-triazol-4-yl)-3-methyl-1H-indole-6-carboxamide;-   1-benzyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indoline-6-carboxamide;-   1-(2-cyclopentyl-7-methoxy-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone;-   2-(3,5-dichloro-4-pyridyl)-1-[1-(4-methoxybenzyl)-3-methyl-1H-indol-6-yl]-ethanone;-   2-(3,5-dichloro-pyridin-4-yl)-1-[1-(1-toluene-4-sulphonyl)-3-methyl-1H-indol-6-yl]-ethanone;-   1-[1-(4-methoxybenzyl)-3-methyl-1H-indol-6-yl]-2-(4-pyridyl)-ethanone;-   1-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone;-   1,3-bis-(4-pyridyl)-2-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-propan-2-ol;-   7-methoxy-2-methoxymethyl-4-[2-(4-pyridyl)ethyl]-3H-benzimidazole;-   2-(4-carboxamidobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   [2-(3-chlorophenoxy)-pyridin-3-yl]-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-methanone;-   2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazole;-   4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-2-methoxymethyl-3H-benzimidazole;-   ethyl    5-(2-cyclopropyl-7-methoxy-benzimidazole-4-yl)pyridine-2-carboxylate;-   2-cyclopropyl-7-methoxy-4-(4-morpholinosulphonyl)-3H-benzimidazole;-   1-benzyl-7-methoxy-2-methoxymethyl-4-(2-(4-pyridyl)ethyl)-1H-benzimidazole;-   1-cyclohexylmethyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide;-   1-(2-cyclohexyl)ethyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide;-   1-[3-(cyclohexyl)propyl]-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-heptyl-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)methyl-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydrofuran-2-yl)methyl-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydrofuran-3-yl)-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3-methoxy)cyclopentyl-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(5-chlorothiophen-2-yl)methyl-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3,5-dimethylisoxazol-4-yl)methyl-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(2-methyl-thiazol-4-yl)methyl-1H-indole-6-carboxamide;-   methyl    5-[6-(3,5-dichloro-pyridin-4-ylcarbamoyl)-3-methyl-indol-1-ylmethyl]-furan-2-carboxylate;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)methyl-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(2-morpholin-4-yl)ethyl-1H-indole-6-carboxamide;-   methyl    5-[6-(3,5-dichloro-pyridin-4-ylcarbamoyl)-3-methyl-indole-1-yl]-pentanoate;-   N-(3,5-dichloro-4-pyridyl)-1-(4-trifluorobenzyl)-3-methyl-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(4-methylsulphonylbenzyl)-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-1-(4-methoxycarbonylbenzyl)-3-methyl-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3-nitrobenzyl)-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-1-(naphthalen-2-yl)methyl-3-methyl-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-1-(biphenyl-4-yl)methyl-3-methyl-1H-indole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(1-benzyl-imidazol-2-yl)methyl-1H-indole-6-carboxamide;-   N-(3,5-dichloro-pyridin-4-yl)-3-ethyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;-   N-(3,5-dichloro-pyridin-4-yl)-3-isopropyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;-   N-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxyethyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;-   N-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxyisopropyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;-   N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;-   N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1H-indole-6-carboxamide;-   1-benzyl-4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one;-   4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one;-   1-(4-methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-ethyl)-1H-indole;-   cis- and    trans-[1-(4-methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-vinyl)-1H-indole;-   6-(1-hydroxy-1-phenyl-2-pyridin-4-yl)ethyl-1-(4-methoxybenzyl)-3-methyl-1H-indole;-   [1-(4-methoxy-benzyl)-3-methyl-1H-indol-6-yl]-phenyl methanone;-   N-methoxy-1-(4-methoxybenzyl)-3-methyl-N-methyl-1H-indole-6-carboxamide;-   1-benzyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indazole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-1-(4-methoxybenzyl)-3-methyl-1H-indazole-6-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-4-methoxy-2-methoxymethyl-benzoxazole-7-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-3-isopropyl-1-methyl-1H-indole-5-carboxamide;    and the corresponding pyridine N-oxides, and their prodrugs and    pharmaceutically acceptable salts and solvates (e.g. hydrates)    thereof.

Preferred compounds of the invention include:

-   N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-2,7-dimethoxy-3H-benzimidazole-4-carboxamide;-   2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   N-(3,5-dichloro-4-pyridyl)-2-isopropyl-7-methoxy-3H-benzimidazole-4-carboxamide;-   2-cyclopropyl-N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-3H-benzimidazole-4-carboxamide;-   N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;-   2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazole;-   4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-2-methoxymethyl-3H-benzimidazole;    and the corresponding pyridine N-oxides, and their prodrugs, and    pharmaceutically acceptable salts and solvates (e.g. hydrates)    thereof.

A more preferred compound of the invention is:

-   2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazole;    and its corresponding pyridine N-oxide, and its prodrugs, and    pharmaceutically acceptable salts, and solvates (e.g. hydrates)    thereof.

The compounds of the invention exhibit useful pharmacological activityand accordingly are incorporated into pharmaceutical compositions andused in the treatment of patients suffering from certain medicaldisorders. The present invention thus provides, according to a furtheraspect, compounds of the invention and compositions containing compoundsof the invention for use in therapy.

Compounds within the scope of the present invention exhibit markedpharmacological activities according to tests described in theliterature which tests results are believed to correlate topharmacological activity in humans and other mammals. Detailed in vitroand in vivo procedures are described hereinafter.

Compounds of the invention are inhibitors of tumor necrosis factor,especially TNF-alpha. Thus, in a further embodiment, the presentinvention provides compounds of the invention and compositionscontaining compounds of the invention for use in the treatment of apatient suffering from, or subject to, conditions which can beameliorated by the administration of an inhibitor of TNF, especially ofTNF-alpha. For example, compounds of the present invention are useful injoint inflammation, including arthritis, rheumatoid arthritis and otherarthritic conditions such as rheumatoid spondylitis and osteoarthritis.Additionally, the compounds are useful in the treatment of sepsis,septic shock, gram negative sepsis, toxic shock syndrome, adultrespiratory distress syndrome, asthma and other chronic pulmonarydiseases, bone resorption diseases, reperfusion injury, graft vs. hostreaction, allograft rejection and leprosy. Furthermore, the compoundsare useful in the treatment of infections such as viral infections andparasitic infections, for example malaria such as cerebral malaria,fever and myalgias due to infection, HIV, AIDS, cachexia such ascachexia secondary to AIDS or to cancer.

Compounds of the invention are also cyclic AMP phosphodiesteraseinhibitors, in particular type IV cyclic AMP phosphodiesteraseinhibitors. Thus, in another embodiment of the invention, we providecompounds of the invention and compositions containing compounds of theinvention for use in the treatment of a patient suffering from, orsubject to, conditions which can be ameliorated by the administration ofan inhibitor of cyclic AMP phosphodiesterase, especially type IV cyclicAMP phosphodiesterase. For example, compounds within the presentinvention are useful as bronchodilators and asthma-prophylactic agentsand agents for the inhibition of eosinophil accumulation and of thefunction of eosinophils, e.g. for the treatment of inflammatory airwaysdisease, especially reversible airway obstruction or asthma, and for thetreatment of other diseases and conditions characterised by, or havingan etiology involving, morbid eosinophil accumulation. As furtherexamples of conditions which can be ameliorated by the administration ofinhibitors of cyclic AMP phosphodiesterase such as compounds of theinvention there may be mentioned inflammatory diseases, such as atopicdermatitis, urticaria, allergic rhinitis, psoriasis, rheumatoidarthritis, inflammatory diseases (e.g. ulcerative colitis and Crohn'sdisease), adult respiratory distress syndrome and diabetes insipidus,other proliferative skin diseases such as keratosis and various types ofdermatitis, conditions associated with cerebral metabolic inhibition,such as cerebral senility, multi-infarct dementia, senile dementia(Alzheimer's disease), and memory impairment associated with Parkinson'sdisease, and conditions ameliorated by neuroprotectant activity, such ascardiac arrest, stroke, and intermittent claudication.

Another group of conditions which may be treated with the compounds ofthe present invention includes diseases and disorders of the centralnervous system such as brain trauma, ischaemia, Huntington's disease andtardive dyskinaesia.

Other disease states which may be treated with the compounds of thepresent invention include pyresis, autoimmune diseases (e.g. systemiclupus erythematosus, allergic erythematosus, multiple sclerosis), type Idiabetes mellitus, psoriasis, Beçhet's disease, anaphylactoid purpuranephritis, chronic glomerulonephritis and leukemia.

A special embodiment of the therapeutic methods of the present inventionis the treating of asthma.

Another special embodiment of the therapeutic methods of the presentinvention is the treating of joint inflammation.

According to a further feature of the invention there is provided amethod for the treatment of a human or animal patient suffering from, orsubject to, conditions which can be ameliorated by the administration ofan inhibitor of cyclic AMP phosphodiesterase or of TNF, especiallyTNF-alpha, for example conditions as hereinbefore described, whichcomprises the administration to the patient of an effective amount ofcompound of the invention or a composition containing a compound of theinvention. “Effective amount” is meant to describe an amount of compoundof the present invention effective in inhibiting cyclic AMPphosphodiesterase and/or TNF and thus producing the desired therapeuticeffect.

According to another aspect of the invention, there is provided the useof a compound of the invention in the manufacture of a medicament forthe treatment of a patient suffering from, or subject to, conditionswhich can be ameliorated by the administration of an inhibitor of cyclicAMP phosphodiesterase, especially type IV cyclic AMP phosphodiesterase.

According to a further aspect of the invention, there is provided theuse of a compound of the invention in the manufacture of a medicamentfor the treatment of a patient suffering from, or subject to, conditionswhich can be ameliorated by the administration of an inhibitor of TNF,especially of TNF-alpha.

References herein to treatment should be understood to includeprophylactic therapy as well as treatment of established conditions.

The present invention also includes within its scope pharmaceuticalcompositions comprising at least one of the compounds of the inventionin association with a pharmaceutically acceptable carrier or excipient.

Compounds of the invention may be administered by any suitable means. Inpractice compounds of the present invention may generally beadministered parenterally, topically, rectally, orally or by inhalation,especially by the oral route.

Compositions according to the invention may be prepared according to thecustomary methods, using one or more pharmaceutically acceptableadjuvants or excipients. The adjuvants comprise, inter alia, diluents,sterile aqueous media and the various non-toxic organic solvents. Thecompositions may be presented in the form of tablets, pills, granules,powders, aqueous solutions or suspensions, injectable solutions, elixirsor syrups, and can contain one or more agents chosen from the groupcomprising sweeteners, flavourings, colourings, or stabilisers in orderto obtain pharmaceutically acceptable preparations. The choice ofvehicle and the content of active substance in the vehicle are generallydetermined in accordance with the solubility and chemical properties ofthe active compound, the particular mode of administration and theprovisions to be observed in pharmaceutical practice. For example,excipients such as lactose, sodium citrate, calcium carbonate, dicalciumphosphate and disintegrating agents such as starch, alginic acids andcertain complex silicates combined with lubricants such as magnesiumstearate, sodium lauryl sulphate and talc may be used for preparingtablets. To prepare a capsule, it is advantageous to use lactose andhigh molecular weight polyethylene glycols. When aqueous suspensions areused they can contain emulsifying agents or agents which facilitatesuspension. Diluents such as sucrose, ethanol, polyethylene glycol,propylene glycol, glycerol and chloroform or mixtures thereof may alsobe used.

For parenteral administration, emulsions, suspensions or solutions ofthe products according to the invention in vegetable oil, for examplesesame oil, groundnut oil or olive oil, or aqueous-organic solutionssuch as water and propylene glycol, injectable organic esters such asethyl oleate, as well as sterile aqueous solutions of thepharmaceutically acceptable salts, are used. The solutions of the saltsof the products according to the invention are especially useful foradministration by intramuscular or subcutaneous injection. The aqueoussolutions, also comprising solutions of the salts in pure distilledwater, may be used for intravenous administration with the proviso thattheir pH is suitably adjusted, that they are judiciously buffered andrendered isotonic with a sufficient quantity of glucose or sodiumchloride and that they are sterilised by heating, irradiation ormicrofiltration.

For topical administration, gels (water or alcohol based), creams orointments containing compounds of the invention may be used. Compoundsof the invention may also be incorporated in a gel or matrix base forapplication in a patch, which would allow a controlled release ofcompound through the transdermal barrier.

For administration by inhalation compounds of the invention may bedissolved or suspended in a suitable carrier for use in a nebuliser or asuspension or solution aerosol, or may be absorbed or adsorbed onto asuitable solid carrier for use in a dry powder inhaler.

Solid compositions for rectal administration include suppositoriesformulated in accordance with known methods and containing at least onecompound of the invention. The percentage of active ingredient in thecompositions of the invention may be varied, it being necessary that itshould constitute a proportion such that a suitable dosage shall beobtained. Obviously, several unit dosage forms may be administered atabout the same time. The dose employed will be determined by thephysician, and depends upon the desired therapeutic effect, the route ofadministration and the duration of the treatment, and the condition ofthe patient. In the adult, the doses are generally from about 0.001 toabout 50, preferably about 0.001 to about 5, mg/kg body weight per dayby inhalation, from about 0.01 to about 100, preferably 0.1 to 70, moreespecially 0.5 to 10, mg/kg body weight per day by oral administration,and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg bodyweight per day by intravenous administration. In each particular case,the doses will be determined in accordance with the factors distinctiveto the subject to be treated, such as age, weight, general state ofhealth and other characteristics which can influence the efficacy of themedicinal product.

The compounds according to the invention may be administered asfrequently as necessary in order to obtain the desired therapeuticeffect. Some patients may respond rapidly to a higher or lower dose andmay find much weaker maintenance doses adequate. For other patients, itmay be necessary to have long-term treatments at the rate of 1 to 4doses per day, in accordance with the physiological requirements of eachparticular patient. Generally, the active product may be administeredorally 1 to 4 times per day. Of course, for some patients, it will benecessary to prescribe not more than one or two doses per day.

The compounds of the present invention may also be formulated for use inconjunction with other therapeutic agents such as agents which increasecyclic AMP production including β-agonists and PGE₂. It is to beunderstood that the present invention includes combinations of compoundsof the present invention with one or more of the aforementionedtherapeutic agents.

Compounds of the invention may be prepared by the application oradaptation of known methods, by which is meant methods used heretoforeor described in the literature.

In particular, compounds of the invention in which the moiety R³ isgroup (iv) may be prepared by methods similar to those described in WO94/20455.

Compounds of the invention in which the moiety R³ is group (v) may beprepared by methods similar to those described in WO 94/14800.

Compounds of the invention in which the moiety R³ is group (vi) may beprepared by methods similar to those described in WO 94/14742.

Compounds of the invention in which the moiety R³ is group (vii) may beprepared by methods similar to those described in WO 94/20446.

Compounds of the invention in which the moiety R³ is group (viii) may beprepared by methods similar to those described in WO 94/10118 and WO95/22520.

Compounds of the invention in which the moiety R³ is group (ix) may beprepared by methods similar to those described in WO 93/25517.

Compounds of the invention in which the moiety R³ is group (x) may beprepared by methods similar to those described in EP-A-0470805.

Compounds of the invention in which the moiety R³ is group (xxviii) maybe prepared by methods similar to those described in WO 96/36595, WO96/36596 and WO 96/36611.

Compounds of the invention in which the moiety R³ is group (xxxiii)wherein R²³ is

may be prepared by methods similar to those described in WO 95/14681.

Compounds of the invention in which moiety R³ is group (xxxiii) whereinR²³ is

may be prepared by methods similar to those described in EP-A-0523513.

Compounds of the invention in which moiety R³ is group (xxxiii) whereinR²³ is

may be prepared by methods similar to those described in EP-A-0510562.

Compounds of the invention in which moiety R³ is group (xxxiii) whereinR²³ is

may be prepared by methods similar to those described in EP-A-0428313.

Compounds of the invention in which moiety R³ is group (xxxiii) whereinR²³ is

may be prepared by methods similar to those described in U.S. Pat. No.5,449,686.

Compounds of the invention in which moiety R³ is group (xxxiii) whereinR²³ is

may be prepared by methods similar to those described in WO 95/09624.

Compounds of the invention in which moiety R³ is group (xxxiii) whereinR²³ is

may be prepared by methods similar to those described in WO 93/19749.

Compounds of the invention in which moiety R³ is group (xxxiii) whereinR²³ is

may be prepared by methods similar to those described in WO 95/03794.

Compounds of the invention in which moiety R³ is group (xxxiii) whereinR²³ is

where W is CH₂ and R³⁷ is hydrogen, may be prepared by methods similarto those described in U.S. Pat. No. 5,420,154.

Compounds of the invention in which moiety R³ is group (xxxiii) whereinR²³ is

where W is NR³⁹ and R³⁷ and R³⁹ are as hereinbefore defined, may beprepared by methods similar to those described in EP-A-0511865.

Compounds of the invention in which moiety R³ is group (xxxiii) whereinR²³ is

and R³⁷ is hydrogen or —CO₂Me, may be prepared by methods similar tothose described by R. D. Miller and P. Goelitz, J. Org. Chem., 1981, 46,page 1616-1618.

Compounds of the invention in which moiety R³ is group (xxxiii) whereinR²³ is

and R³⁷ and R³⁹ are as hereinbefore defined, may be prepared by methodssimilar to those described in WO 95/08534.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Green and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1991.

Compounds of this invention may be represented by the formula (Iz):T¹-R³  (Iz)wherein R³ is as hereinbefore defined and T¹ represents a group of theformula:

wherein

R¹, R², A¹, Z¹, n and m are as hereinbefore defined.

In a process (A), compounds of formula (I) wherein R³ represents a—C(═O)—NHR⁶ group in which R⁶ is as hereinbefore defined may be preparedby the reaction of compounds of the general formula (II):T¹-C(═O)X⁶  (II)wherein T¹ is as hereinbefore defined and X⁶ represents an azido,O-benzotriazol-1-yl, or alkoxy group, such as methoxy, or a halogenatom, such as a bromine, or preferably, a chlorine atom, with compoundsof the general formula (III):R⁶NHR⁴⁸  (III)wherein R⁶ is as hereinbefore described, including N-oxides ofheteroaryl groups, and R⁴⁸ represents a hydrogen atom or an alkanoyl,e.g. acetyl group. The reaction may be carried out in the presence of abase such as an alkali metal dialkyldihydroaluminate, e.g. sodiumdiethyldihydroaluminate or an alkali metal hydride, e.g. sodium hydride,or in the presence of trimethylaluminium, optionally in an inertsolvent, or mixture of inert solvents, chosen from for example ahalogenated hydrocarbon (such as dichloromethane), toluene,dimethylformamide, or an ether (e.g. diethyl ether or tetrahydrofuran),preferably at a temperature from 0° C. to the reflux temperature or atthe melting point of the reaction mixture. The use of sodiumdiethyldihydroaluminate is preferred when R⁶ represents a heteroarylgroup containing at least one nitrogen atom.

As another example, in a process (B), compounds of formula (I) whereinR³ represents a —C(═O)—CH₂R⁶ group in which R⁶ is as hereinbeforedefined, together with compounds of formula (I) wherein R³ represents a—C(R¹³)(R¹⁰)C(R¹¹)(R¹⁴)R¹² group in which R¹⁰ and R¹¹ each represents a—(CH₂)_(p)R⁶ group (where R⁶ is as hereinbefore defined and p is 1), R¹²and R¹⁴ represent hydrogen atoms and R¹³ represents a hydroxy group, maybe prepared by the reaction of compounds of the general formula (IV):T¹-CO₂R⁴⁹  (IV)wherein T¹ is as hereinbefore defined and R⁴⁹ represents a C₁₋₅alkylgroup with compounds of the general formula (V):R⁶—CH₃  (V)wherein R⁶ is as hereinbefore defined, in the presence of a strong basesuch as lithium diisopropylamide (usually prepared in situ from butyllithium and diisopropylamine), in an inert solvent, for example anether, e.g. tetrahydrofuran, preferably at a temperature from −65° C. to0° C.

Alternatively compounds of formula (I) wherein R³ represents a—C(═O)—CH₂R⁶ group and R⁶ is as hereinbefore defined, may be prepared bythe oxidation of compounds of the general formula (VI):T¹-CH(OH)CH₂R⁶  (VI)wherein T¹ and R⁶ are as hereinbefore defined, by the application oradaptation of known methods. The oxidation can be carried out, forexample, by reaction with oxalyl chloride and dimethyl sulphoxide, in asolvent such as dichloromethane, and preferably at a temperature lowerthan −65° C. These conditions are especially convenient for thepreparation of compounds wherein Z¹ represents a direct bond or anoxygen atom.

As another example, in a process (C), compounds of formula (I) whereinR³ represents a —C(═O)—R⁶ group and R⁶ is as hereinbefore defined may beprepared by reaction of compounds of formula (I), wherein R³ representsa group —C(═O)—N(CH₃)OCH₃, with compounds of the general formula (VII):R⁶—MgBr  (VII)wherein R⁶ is as hereinbefore defined, in an inert solvent, for examplean ether, e.g. tetrahydrofuran, preferably at a temperature from about0° C. to about reflux temperature.

Alternatively, in a process (D), compounds of formula (I) wherein R³represents a —C(═O)—R⁶ group and R⁶ is as hereinbefore defined may beprepared by reaction of compounds of formula (II), especially where X⁶represents O-benzotriazolyl, with the anion derived from reaction ofcompounds of formula R⁶—Br (where R⁶ is as hereinbefore defined) andbutyllithium. The reaction is carried out in an inert solvent such as anether, e.g. tetrahydrofuran, and at a temperature at about −70° C.

As another example, compounds of formula (I), wherein R³ represents a—CR⁸═C(R⁹)(CH₂)_(p)—R⁶ group and R⁶, R⁸, R⁹ and p are as hereinbeforedefined, may be prepared by the reaction of compounds of formula (VIII):T¹-C(═O)R⁸  (VIII)wherein T¹ and R⁸ are as hereinbefore defined, with the reaction productof a compound of the formula (IX):[(R⁵⁰)₃PCH(R⁹)(CH₂)_(p)R⁶]⁺ X⁻  (IX)wherein R⁹, R⁶ and p are as hereinbefore defined, R⁵⁰ represents anaryl, such as phenyl group, and X represents halo, preferably bromo,with a base such as an alkali metal alkoxide (for example potassiumt-butoxide), or an alkali metal hydride (for example sodium hydride), orbutyl lithium. The reaction is preferably carried out in a solvent suchas dimethylformamide or tetrahydrofuran.

Compounds of formula (I) wherein R³ represents a —C(R¹⁰)═C(R¹¹)R¹² groupand R¹⁰, R¹¹ and R¹² are as hereinbefore defined, may be similarlyprepared by the reaction of compounds of formula (X):T¹-C(═O)R¹⁰  (X)wherein T¹ and R¹⁰ are as hereinbefore defined, with the phosphoraneobtained by treating a compound of the formula (XI):[(R⁵⁰)₃PCH(R¹¹)R¹²]⁺ X⁻  (XI)wherein R¹¹ and R¹² and R⁵⁰ are as hereinbefore defined with a base asdescribed above.

As another example, compounds of formula (I) wherein R³ represents a—CR⁸═C(R⁹)(CH₂)_(p)—R⁶ group, where R⁶, R⁸, R⁹ and p are as hereinbeforedefined, may be prepared by the reaction of compounds of formula (VIII),wherein T¹ is as hereinbefore defined, with the reaction product of acompound of the formula (XII):(R⁵¹O)₂P(═O)CH(R⁹)(CH₂)_(p)R⁶  (XII)wherein R⁶, R⁹ and p are as hereinbefore defined and R⁵¹ represents aC₁₋₄alkyl group, with a base such as an alkali metal alkoxide (forexample potassium t-butoxide), or an alkali metal hydride (for examplesodium hydride). The reaction is preferably carried out in a solventsuch as dimethylformamide or tetrahydrofuran. Compounds of formula (I)wherein R³ represents a —C(R¹⁰)═C(R¹¹)R¹² group and R¹⁰, R¹¹ and R¹² areas hereinbefore defined may be prepared in a similar manner to thatdescribed above from compounds of formula (X), wherein T¹ and R¹⁰ are ashereinbefore defined, and compounds of formula (XIII):(R⁵¹O)₂P(═O)CH(R¹¹)R¹²  (XIII)wherein R¹¹, R¹² and R⁵¹ are as hereinbefore defined.

As another example, compounds of formula (I) wherein R³ represents a—C(R¹⁰)═C(R¹¹)R¹² group where R¹⁰, R¹¹ and R¹² are as hereinbeforedefined may also conveniently be prepared from compounds of formula(XIV):T¹-C(R¹⁰)(OH)CH(R¹¹)R¹²  (XIV)wherein T¹, R¹⁰, R¹¹ and R¹² are as hereinbefore defined, by dehydrationusing an acid such as a Lewis acid (e.g. thionyl bromide) at an elevatedtemperature, for example the reflux temperature, optionally in thepresence of a suitable base such as 1,8-diazabicyclo-[5.4.0]undec-7-ene.

Compounds of formula (I) wherein R³ represents —C(R⁸)═C(R⁹)(CH₂)_(p)R⁶where R⁶, R⁸, R⁹ and p are as hereinbefore defined may be prepared bydehydration of compounds of formula (XV):T¹-C(R⁸)(OH)CH(R⁹)(CH₂)_(p)R⁶  (XV)wherein T¹, R⁶, R⁸, R⁹ and p are as hereinbefore defined, using an acidsuch as a Lewis acid (e.g. thionyl bromide) at an elevated temperature,for example the reflux temperature, optionally in the presence of asuitable base such as 1,8-diazabicyclo-[5.4.0]undec-7-ene. Alternativelythe dehydration may be carried out using an acid catalyst, such as4-toluenesulphonic acid, in an inert solvent, such as benzene, at atemperature from about 0° C. to about reflux temperature.

As another example, compounds of formula (I) wherein R³ represents a—C(R¹³)(R¹⁰)C(R¹¹)(R¹⁴)R¹² group where R¹⁰, R¹¹ and R¹² are ashereinbefore defined, and R¹³ and R¹⁴ each represent a hydrogen atom,may be prepared by hydrogenation of compounds of the general formula (I)wherein R³ represents a —C(R¹⁰)═C(R¹¹)R¹² where R¹⁰, R¹¹ and R¹² are ashereinbefore defined. The hydrogenation may be carried out usinghydrogen in the presence of a suitable metal catalyst, e.g. platinum orpalladium optionally supported on an inert carrier such as carbon,preferably in a solvent such as methanol or ethanol. Compounds offormula (I) wherein R³ represents a —C(R⁸)(R¹⁵)CH(R⁹)(CH₂)_(p)—R⁶ groupwhere R⁸, R⁹ and p are as hereinbefore defined and R¹⁵ represents ahydrogen atom, may be prepared in a similar manner to that describedabove by hydrogenation of compounds of the general formula (I) whereinR³ represents a —C(R⁸)═C(R⁹)(CH₂)_(p)R⁶ where R⁸, R⁹ and p are ashereinbefore defined.

Compounds of formula (I), wherein R³ represents a—C(R⁸)(R¹⁵)CH(R⁹)(CH₂)_(p)—R⁶ group where R⁶ is as hereinbefore definedand R⁸, R⁹ and R¹⁵ represent hydrogen atoms and p is zero, may beprepared by reduction of compounds of the general formula (I) wherein R³represents a —C(═O)—CH₂R⁶, where R⁶ is as hereinbefore defined. Thereduction may be carried out with hydrazine hydrate, in the presence ofan alkali metal hydroxide, such a potassium hydroxide, in an inertsolvent, such as diethylene glycol, at a temperature up to about 100° C.

As another example, compounds of formula (I) wherein R³ represents a R⁶group may be prepared by the reaction of compounds of the generalformula (XVI):T¹-B(OH)₂  (XVI)wherein T¹ is as hereinbefore defined, with a compound of the generalformula (XVII):R⁶—X⁷  (XVII)wherein R⁶ is as hereinbefore described and X⁷ represents a halogen atomfor example a bromine or chlorine atom, or a triflate group, in thepresence of a complex metal catalyst such astetrakis(triphenylphosphine)palladium(0).

Alternatively compounds of formula (I) wherein R³ represents a R⁶ groupmay be similarly prepared by the reaction of compounds of the generalformula (XVIII):T¹-X⁷  (XVIII)wherein T¹ and X⁷ are as hereinbefore defined, with a compound of thegeneral formula (XIX):R⁶—B(OH)₂  (XIX)wherein R⁶ is as hereinbefore defined in the presence of a complex metalcatalyst such as tetrakis(triphenylphosphine)palladium(0).

Compounds of formula (I) wherein R³ represents a R⁶ group may also beprepared by reaction of compounds of formula (XVIII) wherein T¹ is ashereinbefore defined and X⁷ is a bromine atom, with a solution ofbutyllithium in hexane, in an inert solvent such as tetrahydrofuran, ata temperature at about −70° C., followed by reaction with tributyltinchloride and subsequent reaction of the tributyltin intermediate withcompounds of formula (XVII) wherein R⁶ is as hereinbefore defined and X⁷is a bromine atom, in the presence of bis(dibenzylidene)acetonepalladium(0) and triphenylphosphine in dimethylformamide at atemperature up to about 120° C.

As another example, compounds of formula (I) wherein R³ represents a—NHC(═O)R⁶ group where R⁶ is as hereinbefore defined, may be prepared bythe reaction of compounds of the general formula (XX):T¹-NH₂  (XX)wherein T¹ is as hereinbefore defined with compounds of formula (XXII):R⁶C(═O)X⁸  (XXI)wherein R⁶ is as hereinbefore defined and X⁸ represents an azido groupor a halogen atom, e.g. bromine or, preferably, chlorine atom, are ashereinbefore defined, preferably in the presence of a base such as atertiary amine, e.g. triethylamine, preferably in a solvent such asdichloromethane.

As another example, compounds of formula (I) wherein R³ represents a—C(CH₃)═N—OC(=0)NH₂ group may be prepared by the reaction of compoundsof the general formula (XXII):T¹-C(═NOH)CH₃  (XXII)wherein T¹ is as hereinbefore defined, with sodium cyanate in an inertsolvent such as dichloromethane in the presence of an acid such asacetic acid or trifluoroacetic acid at a temperature at about ambienttemperature.

As another example, compounds of formula (I) wherein R³ represents a—C(═O)—N(Me)OCH₃ group may be prepared by the reaction of compounds ofthe general formula (II), wherein T¹ is as hereinbefore defined and X⁶is a halogen atom, such as a chlorine atom, withN-methyl-O-methylhydroxylamine in an inert solvent such asdimethylformamide.

As another example, compounds of formula (I) wherein R³ represents a—C≡C—R⁶ group where R⁶ is as hereinbefore defined, may be prepared bythe reaction of compounds of the general formula (XXIII):T¹-I  (XXIII)wherein T¹, is as hereinbefore defined, with acetylenes of the generalformula (XXIV):R⁶C≡CH  (XXIV)wherein R⁶ is as hereinbefore defined. Preferably the reaction iscarried out with the aid of a catalyst, e.g. palladium on carbon andcuprous iodide, preferably with the aid of a base such as a tertiaryamine, e.g. triethylamine, preferably in a solvent such asdimethylformamide.

As another example, compounds of formula (I) wherein R³ represents a—CH₂—C(═O)—R⁶ group where R⁶ is as hereinbefore defined may be preparedby oxidation of compounds of the general formula (XXV):T¹-CH₂CH(OH)R⁶  (XXV)wherein T¹ and R⁶ are as hereinbefore defined. The oxidation mayconveniently be carried out, for example, by reaction with oxalylchloride and dimethyl sulphoxide, in a solvent such as dichloromethane,and preferably at a temperature lower than −65° C. Alternatively, theoxidation may be carried out by reaction with chromium trioxide in thepresence of 3,5-dimethylpyrazole.

As another example, compounds of formula (I) wherein R³ represents a—C(═O)—C(═O)R⁶ group where R⁶ is as hereinbefore defined may be preparedby the oxidation of compounds of formula (I) wherein R³ represents a—C(═O)—CH₂R⁶ group where R⁶ is as hereinbefore defined. The oxidationmay be carried out, for example, by reaction with pyridinium dichromate,preferably in a solvent such as dichloromethane. This reaction isparticularly suitable for the preparation of compounds wherein R⁶represents a heteroaryl, for example an optionally substituted pyridyl,group.

As another example, compounds of formula (I) wherein R³ represents—CH₂—NHR⁶ group where R⁶ is as hereinbefore defined may be prepared bythe reaction of compounds of the general formula (XXVI):T¹-C(═O)H  (XXVI)wherein T¹ is as hereinbefore defined, with compounds of formula (III)wherein R⁶ is as hereinbefore defined and R⁴⁸ is hydrogen, followed byreduction with sodium cyanoborohydride. This reaction is especiallysuitable for the preparation of compounds wherein R⁶ represents anoptionally substituted phenyl or naphthyl group.

Alternatively, compounds of formula (I) wherein R³ represents —CH₂—NHR⁶group where R⁶ is as hereinbefore defined may be prepared by thereaction of compounds of the general formula (XXVII):T¹-CH₂X⁹  (XXVII)

wherein T¹ is as hereinbefore defined and X⁹ represents halogen,preferably a bromine atom, with compounds of formula (III) wherein R⁶ isas hereinbefore defined and R⁴⁸ is hydrogen. The reaction preferablytakes place in the presence of a base such as sodium hydride. Thereaction is especially suitable for the preparation of compounds whereinR⁶ represents an optionally substituted heteroaryl group.

As another example, compounds of formula (I) wherein R³ represents—CH₂—OR⁶ group where R⁶ is as hereinbefore defined may be prepared bythe reaction of compounds of the general formula (XXVII) wherein T¹ andX⁹ are as hereinbefore defined with compounds of formula (XXVIII):R⁶—OH  (XXVIII)wherein R⁶ is as hereinbefore defined, preferably with the aid of a basesuch as an alkali metal alkoxide, e.g. potassium t-butoxide.

Alternatively compounds of formula (I) wherein R³ represents a —CH₂—OR⁶group where R⁶ is as hereinbefore defined may be prepared by thereaction of compounds of the general formula (XXIX):T¹-CH₂OH  (XXIX)wherein T¹ is as hereinbefore defined, with compounds of formula (XVII)wherein R⁶ and X⁷ are as hereinbefore defined, preferably with the aidof a base such as an alkali metal alkoxide, e.g. potassium t-butoxide.The reaction is preferably carried out in a solvent such astetrahydrofuran.

Alternatively compounds of formula (I) wherein R³ represents a —CH₂—OR⁶group where R⁶ is as hereinbefore defined may be prepared by reaction ofcompounds of the general formula (XXIX) with compounds of formula(XXVIII)

wherein R⁶ is as hereinbefore defined, in the presence of a dialkylazodicarboxylate, such as diethyl azodicarboxylate, andtriphenylphosphine, preferably in a dry ethereal solvent, e.g. diethylether or tetrahydrofuran, preferably at or near room temperature.

As another example, compounds of formula (I) wherein R³ represents a—CH₂—SR⁶ group where R⁶ is as hereinbefore defined may be prepared bythe reaction of compounds of the general formula (XXVIII), wherein T¹and X⁹ are as hereinbefore defined with compounds of the general formula(XXX):R⁶—SH  (XXX)wherein R⁶ is as hereinbefore defined, preferably with the aid of a basesuch as an alkali metal carbonate, e.g. potassium carbonate.

As another example, compounds of formula (I) wherein R³ represents a—CF₂—OR⁶ group where R⁶ is as hereinbefore defined may be prepared bythe reaction of compounds of the general formula (XXXI):T¹-CF₂Br  (XXXI)with compounds of the general formula (XXVIII) wherein R⁶ is ashereinbefore defined, preferably with the aid of a base such as sodiumhydride, preferably in a solvent such as dimethylformamide.

As another example, compounds of formula (I) wherein R³ represents a—NH—CH₂R⁶ group where R⁶ is as hereinbefore defined may be prepared bythe reaction of compounds of the general formula (XX) wherein T¹ is ashereinbefore defined, with compounds of the general formula (XXXII):R⁶CHO  (XXXII)wherein R⁶ is as hereinbefore defined, in the presence of a reducingagent such as sodium cyanoborohydride.

As another example, compounds of formula (I) wherein R³ represents a—O—CH₂R⁶ group where R⁶ is as hereinbefore defined may be prepared bythe reaction of compounds of the general formula (XXXIII):T¹-OH  (XXXIII)wherein T¹ is as hereinbefore defined, with compounds of the generalformula (XXXIV):R⁶CH₂X¹⁰  (XXXIV)wherein R⁶ is as hereinbefore defined and X¹⁰ represents hydroxy or ahalogen atom. When X¹ represents hydroxy the reaction is convenientlycarried out in the presence of a dialkyl azodicarboxylate, such asdiethyl azodicarboxylate, and triphenylphosphine, preferably in a dryethereal solvent, e.g. diethyl ether or tetrahydrofuran, preferably ator near room temperature. When X¹⁰ represents a halogen atom, especiallya chlorine atom, the reaction is preferably carried out in the presenceof a base such as an alkali metal carbonate, e.g. potassium carbonate,preferably in an solvent such as dimethylformamide, and at a temperaturefrom about room temperature to about 80° C.

As another example, compounds of formula (I) wherein R³ represents a—S—CH₂R⁶ group where R⁶ is as hereinbefore defined may be prepared bythe reaction of compounds of the general formula (XXXV):T¹-SH  (XXXV)wherein T¹ is as hereinbefore defined, with compounds of formula (XXXIV)wherein R⁶ is as hereinbefore defined and X¹⁰ is a halogen atom,preferably a bromine atom. The reaction is preferably carried out in thepresence of a base such as an alkali metal alkoxide, e.g. sodiummethoxide.

As another example, compounds of formula (I) wherein R³ represents a—O—CF₂R⁶ group where R⁶ is as hereinbefore defined may be prepared bythe reaction of compounds of the general formula (XXXIII) wherein T¹ isas hereinbefore defined with compounds of the general formula (XXXVI):R⁶CF₂Br  (XXXVI)wherein R⁶ is as hereinbefore defined, preferably with the aid of a basesuch as sodium hydride, preferably in a solvent such asdimethylformamide.

As another example, compounds of formula (I) wherein R³ represents a—O—C(═O)R⁶ group where R⁶ is as hereinbefore defined may be prepared bythe reaction of compounds of the general formula (XXXIII), wherein T¹ isas hereinbefore defined, with compounds of the general formula (XXI)wherein R⁶ is as hereinbefore defined, and X⁸ represents a halogen atom,for example a bromine or, preferably, a chlorine atom, preferably in thepresence of a base such as a tertiary amine, e.g. triethylamine,preferably in a solvent such as dichloromethane.

As another example, compounds of formula (I) wherein R³ represents atrans —N═N—R⁶ group where R⁶ is as hereinbefore defined may be preparedby the reaction of compounds of the general formula (XXXVII):T¹-N₂ ⁺ BF₄—  (XXXVII)wherein T¹ is as hereinbefore defined, with compounds of the generalformula (XXXVIII):R⁶H  (XXXVIII)wherein R⁶ is as hereinbefore defined, preferably with the aid of a basesuch as lithium diisopropylamide.

As another example, compounds of formula (I) wherein R³ represents a—NH—SO₂R⁶ group where R⁶ is as hereinbefore defined may be prepared bythe reaction of compounds of the general formula (XX), wherein T¹ is ashereinbefore defined, with compounds of the general formula (XXXIX):R⁶SO₂X¹¹  (XXXIX)wherein R⁶ is as hereinbefore defined and X¹¹ represents a halogen,preferably chlorine, atom, preferably with the aid of a base such as atertiary amine, e.g. triethylamine, preferably in a solvent such astetrahydrofuran.

As another example, compounds of formula (I) wherein R³ represents a—SO₂—NR²¹R²² group where R²¹ and R²² are as hereinbefore defined may beprepared by the reaction of compounds of the general formula (XXXX):T¹SO₂Cl  (XXXX)wherein T¹ is as hereinbefore defined with compounds of the generalformula (XXXXI):R²¹—NH—R²²  (XXXXI)wherein R²¹ and R²² are as hereinbefore defined, preferably with the aidof a base such as a tertiary amine, e.g. triethylamine, preferably in asolvent such as tetrahydrofuran.

As another example, compounds of formula (I) wherein R³ represents a—C(═O)—C(═O)—NHR⁶ group where R⁶ is as hereinbefore defined may beprepared by the reaction of compounds of the general formula (XXXXII):T¹-COCOOH  (XXXXII)wherein T¹ is as hereinbefore defined, with thionyl chloride in an inertsolvent such as dichloromethane, followed by reaction with compounds offormula (III) wherein R⁶ is as hereinbefore defined and R⁴⁸ is hydrogen.

As another example, compounds of formula (I) wherein R³ represents a—NH—CO—OR⁶ group where R⁶ is as hereinbefore defined may be prepared bythe reaction of compounds of the general formula (XXXXIII):T¹-NCO  (XXXXIII)wherein T¹ is as hereinbefore defined, with compounds of formula(XXVIII) wherein R⁶ is as hereinbefore defined, preferably with the aidof a base such as a tertiary amine, e.g. triethylamine, preferably in asolvent such as dichloromethane.

As another example, compounds of formula (I) wherein R³ represents a—O—CO—NHR⁶ group where R⁶ is as hereinbefore defined may be prepared bythe reaction of compounds of the general formula (XXXIII) wherein T¹ isas hereinbefore defined, with compounds of formula (III) wherein R⁶ isas hereinbefore defined and R⁴⁸ is hydrogen, together with phosgene or asource thereof, preferably, bis(trichloromethyl)carbonate, preferablywith the aid of a base such as a tertiary amine, e.g. triethylamine,preferably in a solvent such as dichloromethane.

As another example, compounds of formula (I) wherein R³ represents a—NH—CO—NHR⁶ group where R⁶ is as hereinbefore defined may be prepared bythe reaction of compounds of the general formula (XX), wherein T¹ is ashereinbefore defined with compounds of the general formula (XXXXIV):R⁶NCO  (XXXXIV)wherein R⁶ is as hereinbefore defined, preferably in the presence of abase such as a tertiary amine, e.g. triethylamine, preferably in asolvent such as dichloromethane.

According to a further feature of the present invention, compounds offormula (I) wherein R³ represents a —NH—CO—NHR⁶ group where R⁶ is ashereinbefore defined may be prepared by the reaction of compounds offormula (XX) wherein T¹ is as hereinbefore defined with compounds offormula (III) wherein R⁶ is as hereinbefore defined and R⁴⁸ is hydrogen,together with phosgene or a source thereof. The reaction is preferablycarried out by reacting the compound of formula (XX) with phosgene or,preferably, bis(trichloromethyl) carbonate, and by then reacting theproduct of that reaction with the anion derived from the compound offormula (III), for example by reaction with a base such as sodiumhydride. The reactions may be preferably carried out in suitablesolvents such as dichloromethane and tetrahydrofuran.

According to a further feature of the present invention, compounds offormula (Ia) wherein

A¹, R¹, R², R³, Q¹ and Z¹ are as hereinbefore defined, (with the provisothat when A¹ is a direct bond then R² is alkyl, cycloalkyl, aryl, orheteroaryl), may be prepared by reaction of compounds of formula(XXXXV):

wherein A¹, R¹, R², R³, Q¹ and Z¹ are as hereinbefore defined, (with theproviso that when A¹ is a direct bond then R² is alkyl, cycloalkyl,aryl, or heteroaryl), with sodium hypochlorite in the presence of anaqueous acid such as dilute hydrochloric acid, in an alcohol, such asmethanol, and at a temperature at about ambient temperature, followed bytreatment with an alkali metal carbonate, such as sodium carbonate, at atemperature of about reflux temperature.

According to a further feature of the present invention, compounds offormula (Ia), wherein

A¹, R¹, R², R³, Q¹ and Z¹ are as hereinbefore defined, (with the provisothat when A¹ is a direct bond then R² is alkyl, cycloalkyl, aryl, orheteroaryl), may be prepared by reaction of compounds of formula(XXXXVI):

wherein R¹, R³, Q¹ and Z¹ are as hereinbefore described, with compoundsof formula (XXXXVII):R²A¹C(═O)X¹²  (XXXXVII)wherein R² and A¹ are as hereinbefore defined, (with the proviso thatwhen A¹ is a direct bond then R² is alkyl, cycloalkyl, aryl, orheteroaryl), and X¹² represents a hydroxy group or a halogen atom,preferably a chlorine atom. When X¹² represents a hydroxy group thereaction is preferably carried out in the hydrochloric acid at atemperature at about 125° C. When X¹² represents a halogen atom thereaction is preferably carried out in an inert solvent, such asdichloromethane, optionally in the presence of triethylamine and at atemperature from about 0° C. to about ambient temperature, followed byreaction of the product with acetic acid at a temperature at aboutreflux.

According to a further feature of the present invention, compounds offormula (Ia), wherein R¹, R³, Q¹ and Z¹ are as hereinbefore defined, R²represents a C₁₋₅alkoxy group optionally substituted by one or morefluorine atoms, A¹ represents a direct bond and

may be prepared by reaction of compounds of formula (XXXXVI) wherein R¹,R³, Q¹ and Z¹ are as hereinbefore described, with compounds of formula(XXXXVIII):(R⁴⁹O)₄C  (XXXXVIII)wherein R⁴⁹ is a C₁₋₅alkyl group optionally substituted by one or morefluorine atoms. The reaction may conveniently be carried out in aceticacid at a temperature up to about reflux temperature.

As another example, compounds of formula (Ia) wherein

R¹, R³, Q¹ and Z¹ are as hereinbefore described, R² is alkylthio,arylthio or arylalkylthio and A¹ represents a direct bond, may beprepared by reaction of compounds of formula (XXXXIX):

wherein

R¹, R³, Q¹ and Z¹ are as hereinbefore described, with the appropriatealkyl- or aryl- or arylalkylthiol. The reaction may conveniently becarried out in an inert solvent such as methanol or dimethylformamide,at a temperature from about room temperature to about 80° C., optionallyin the presence of an alkali metal carbonate, such as potassiumcarbonate.

Alternatively compounds of formula (Ia) wherein

R¹, R³, Q¹ and Z¹ are as hereinbefore described, R² represents alkylthioor arylalkylthio and A¹ represents a direct bond, may be prepared byreaction of compounds of formula (L):

wherein R¹, R³,

Q¹ and Z¹ are as hereinbefore described, with the appropriate alkyl- orarylalkylhalide. The reaction may conveniently be carried out in aninert solvent such as methanol or dimethylformamide, at a temperaturefrom about room temperature to about 80° C., optionally in the presenceof an alkali metal carbonate, such as potassium carbonate.

As another example, compounds of formula (Ia) wherein

R¹, R³, Q¹ and Z¹ are as hereinbefore described, R² represents NR⁴R⁵where R⁴ and R⁵ are as hereinbefore described and A¹ represents a directbond, may be prepared by reaction of compounds of formula (XXXXIX)wherein

R¹, R³, Q¹ and Z¹ are as hereinbefore described, with compounds offormula (LI):HNR⁴R⁵  (LI)wherein R⁴ and R⁵ are as hereinbefore described. The reaction mayconveniently be carried out in an inert solvent for example an alcoholsuch as isopropanol, at a temperature from about room temperature toabout 80° C., optionally in the presence of an alkali metal carbonate,such as potassium carbonate.

As another example, compounds of formula (Ia) wherein

R¹, R³, Q¹ and Z¹ are as hereinbefore described, R² represents —C(═O)R⁵,in which R⁵ is aryl or heteroaryl, and A¹ represents a direct bond, maybe prepared by reaction of compounds of formula (LII):

wherein R¹, R³,

Q¹ and Z¹ are as hereinbefore described, with compounds of formula(LIII):R⁵C(═O)X¹³  (LIII)wherein R⁵ is aryl or heteroaryl and X¹³ is a chlorine atom. Thereaction may conveniently be carried out in an inert solvent for exampledimethylformamide, at a temperature up to about 150° C., under vacuo,optionally in the presence of triethylamine.

As another example, compounds of formula (I) wherein R³ represents a

may be prepared by reaction of compounds of formula (I) wherein R³represents a

in which R⁵² is a methyl or ethyl group, with hydroxylaminehydrochloride in the presence of sodium methoxide, in a solvent such asan alcohol, for example methanol, and at a temperature at about roomtemperature.

As another example, compounds of formula (I) wherein T¹ is ashereinbefore described and the moiety R³ represents a

group may be prepared by reaction of compounds of formula (VIII) whereinR⁸ is methyl, with glyoxylic acid monohydrate at about 100° C. to 150°C., followed by treatment with hydrazine hydrate at reflux.

As another example, compounds of formula (I) wherein R³ represents a

group may be prepared by reaction of compounds of formula (LIV):T¹-C(CN)[(CH₂)₂CO₂R⁵²]₂  (LIV)wherein T¹ is as hereinbefore described and R⁵² is a methyl or an ethylgroup, with an alkali metal hydride, for example sodium hydride, in aninert solvent, such as 1,2-dimethoxyethane, at a temperature at aboutreflux temperature, followed by heating the product with a mixture ofconcentrated hydrochloric acid and 20% sulphuric acid in ethanol atreflux temperature.

As another example, compounds of formula (I) wherein R³ represents a

group may be prepared by reaction of compounds of formula (I), whereinT¹ is as hereinbefore described and the moiety R³ represents a

group, with diethyl aluminium cyanide in an inert solvent, such astoluene, and at a temperature at about room temperature.

Compounds of formula (I), wherein R³ represents a

group may be prepared by reaction of compounds of formula (XVIII),wherein T¹ is as hereinbefore described and X⁷ is a bromine atom, withan alkyl lithium, such as n-butyl lithium at −78° C., in an inertsolvent, such as tetrahydrofuran, followed by reaction with3-methoxycyclohex-2-enone (prepared according to the method of A. J.Pearson et al., J. Org. Chem., 1984, 49, pages 3887-3891) at atemperature at about 0° C.

As another example, compounds of formula (I) wherein R³ represents a

group may be prepared by hydrolysis of compounds of formula (I) whereinR³ represents a

group, with an alkali metal hydroxide such as potassium hydroxide in anaqueous alcohol such as aqueous methanol and at a temperature from aboutroom temperature to about reflux.

Compounds of formula (I), wherein R³ represents a

group, may be prepared by reaction of compounds of formula (I), whereinR³ represents a

group, with triflic anhydride in the presence of an appropriate tertiaryamine base, or with lithium diisopropylamide at −78° C., in an inertsolvent such as tetrahydrofuran, followed by treatment with N-phenyltrifluorosulphonimide. The resulting enol triflate may then be reactedwith carbon monoxide in an alcohol such as methanol, optionally mixedwith dimethylformamide, in the presence of an amine, such astriethylamine, and an appropriate palladium catalyst, such astetrakis(triphenylphosphine)palladium, at a temperature at about roomtemperature.

As another example, compounds of formula (I) wherein R³ represents a

group, in which R³⁹ is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl, may be prepared by reaction of compounds of formula(LV):T¹-CH═CH—CO₂H  (LV)wherein T¹ is as hereinbefore described, with a hydrazine of formula(LVI):R³⁹NH—NH₂  (LVI)wherein R³⁹ is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl. The reaction is preferably carried out in an inertsolvent, such as toluene, at a temperature at about 100° C.

As another example, compounds of formula (I) wherein R³ represents a

group may be prepared by reduction of compounds of the general formula(LVII):T¹-CH(CH₂NO₂)CH₂CO₂R⁴⁹  (LVII)wherein T¹ and R⁴⁹ are as hereinbefore described, followed by hydrolysiswith sodium hydroxide. The reduction may be carried out using hydrogenin the presence of Raney Nickel preferably in a solvent such as methanolor ethanol and at a temperature at about room temperature.

As another example, compounds of formula (I) wherein R³ represents agroup

may be prepared by oxidation of compounds of formula (LVIII):T¹-CH(NHCO₂Me)CH₂CH₂CH₂OH  (LVIII)wherein T¹ is as hereinbefore described, with Jones reagent in acetoneat room temperature.

According to a further feature of the present invention, in a process(E), compounds of the present invention of formula (Ia) wherein R¹, R²,R³, A¹, Q¹ and Z¹ are as hereinbefore defined, and

may be prepared by deprotection of compounds of formula (LIX):

wherein R¹, R², R³, A¹, Q¹ and Z¹ are as hereinbefore defined and{circle over (P)} is a suitable protecting group, for example a2-trimethylsilanyl-ethoxymethyl group. When {circle over (P)} is a2-trimethylsilanyl-ethoxymethyl group the deprotection reaction mayconveniently be carried out by treatment with hydrochloric acid, in analcohol, such as ethanol, and at a temperature at about refluxtemperature. This process is particularly convenient for compounds offormula (Ia) wherein R³ is a group —O—CH₂—R⁶ in which R⁶ is ashereinbefore defined.

According to a further feature of the present invention, in a process(F) compounds of the invention may be prepared by interconversion ofother compounds of the invention.

For example compounds of the invention containing an imino group may bealkylated with an alkyl halide, arylalkyl halide or heteroarylalkylhalide. Thus compounds of formula (Ia) wherein

and R⁵ represents C₁₋₄straight- or branched-chain alkyl, anarylC₁₋₄alkyl or a heteroarylC₁₋₄alkyl group may be prepared by reactionof compounds of formula (Ia) wherein

with a C₁₋₄straight- or branched-chain alkyl halide, an arylC₁₋₄alkylhalide or a heteroarylC₁₋₄alkyl halide. The alkylation may for examplebe carried out in the presence of a base, such as an alkali metalhydride, e.g. sodium hydride, in dimethylformamide, or dimethylsulphoxide, at a temperature from about 0° C. to about 100° C.

As another example of the interconversion process, compounds of theinvention containing an imino group may be acylated with an acyl halide,aroyl halide or heteroaroyl halide. The acylation may for example becarried out in the presence of a suitable base, such as triethylamine orpyridine, optionally in dimethylformamide, at a temperature from about0° C. to about 100° C.

As another example of the interconversion process, compounds of theinvention containing a heterocyclic group wherein the hetero atom is anitrogen atom may be oxidised to their corresponding N-oxides. Thisinterconversion is especially convenient for the preparation ofcompounds of the invention wherein Z¹ represents an oxygen atom andwherein neither R² or R³ contain an oxidisable groups such as athioether. The oxidation may conveniently be carried out by means ofreaction with a mixture of hydrogen peroxide and an organic acid, e.g.acetic acid, preferably at or above room temperature, for example at atemperature of about 60-90° C. Alternatively, the oxidation may becarried out by reaction with a peracid, for example peracetic acid orm-chloroperoxybenzoic acid, in an inert solvent such as chloroform ordichloromethane, at a temperature from about room temperature to reflux,preferably at elevated temperature. The oxidation may alternatively becarried out by reaction with hydrogen peroxide in the presence of sodiumtungstate at temperatures between room temperature and about 60° C.

As another example of the interconversion process, an N-oxide groupwithin a compound of formula (I) may be reduced to a nitrogen atom. Moreparticularly, one or more of the N-oxide groups in a compound of formula(I) wherein Q¹ represents a nitrogen atom in its oxidised form and R²and/or R³ represents a heteroaryl group containing one or more nitrogenring atoms in its oxidised form, may be reduced to a nitrogen atom. Thereduction of an N-oxide group may be carried out by reaction withdiphosphorus tetraiodide in an inert solvent, such as dichloromethane,preferably at or near room temperature, or by reaction with achlorotrialkylsilane, preferably chlorotrimethylsilane, in the presenceof zinc and an alkali metal iodide, e.g. potassium iodide, in an inertsolvent, e.g. acetonitrile, at a temperature between about 0° C. andabout room temperature, preferably below room temperature.

According to a further example of the interconversion process, compoundsof the invention containing hydroxy moieties may be converted to estersby the application or adaptation of known methods of esterification, forexample, by reaction with an acid chloride (prepared by treatment of theappropriate acid with thionyl chloride or oxalyl chloride), preferablyin the presence of a base, for example a tertiary amine, e.g.triethylamine. Alternatively, compounds of the invention containinghydroxy moieties may be reacted with the appropriate acid in thepresence of a dialkyl azodicarboxylate, such as diethylazodicarboxylate, and triphenylphosphine, preferably in a dry etherealsolvent, e.g. diethyl ether or tetrahydrofuran, preferably at or nearroom temperature.

As another example of the interconversion process, compounds of theinvention containing hydroxy moieties may be prepared by hydrolysis ofcorresponding esters of the invention. The hydrolysis may convenientlybe carried out by alkaline hydrolysis using a base, such as an alkalimetal hydroxide or carbonate, in the presence of an aqueous/organicsolvent mixture, using organic solvents such as dioxan, tetrahydrofuranor methanol, at a temperature from about ambient to about reflux. Thehydrolysis of the esters may also be carried out by acid hydrolysisusing an inorganic acid, such as hydrochloric acid, in the presence ofan aqueous/inert organic solvent mixture, using organic solvents such asdioxan or tetrahydrofuran, at a temperature from about 50° C. to about80° C.

As another example of the interconversion process, compounds of formula(I) wherein R³ represents a group containing R⁶ which is substituted bya formyl group may be prepared by oxidising the corresponding compoundsof formula (I) wherein R³ represents a group containing R⁶ which issubstituted by a hydroxymethyl group for example with oxalyl chlorideand dimethyl sulphoxide, in a solvent such as dichloromethane, andpreferably at a temperature lower than about −65° C., or, preferably, byreaction with a complex of sulphur trioxide with an amine such aspyridine, preferably in the presence of an amine such as triethylamine,preferably at about room temperature.

As another example of the interconversion process, compounds of formula(I) wherein R³ represents a group containing R⁶ which is substituted byan amino group may be prepared by reducing the corresponding compoundsof formula (I) wherein R³ represents a group containing R⁶ which issubstituted by a nitro group, preferably with iron in acidic conditions,such as in acetic acid, preferably at or above room temperature, moreespecially at the reflux temperature. Alternatively the reduction may becarried out by reaction with hydrazine hydrate in the presence of ferricchloride and activated carbon, conveniently in a solvent such asmethanol, at temperatures from about 25° C. to about 80° C.

As another example of the interconversion process, compounds of formula(I) wherein R³ represents a group containing R⁶ which is substituted byan acylamino or aroylamino group may be prepared from compounds offormula (I) wherein R³ represents a group containing R⁶ which issubstituted by an amino group, preferably by means of reaction with theappropriate acid halide or acid anhydride in the presence of a tertiarybase, such as triethylamine, optionally in an inert solvent, andpreferably at a temperature from about 0° C. to reflux.

As another example of the interconversion process, compounds of formula(I) wherein R³ represents a group containing R⁶ which is substituted bya carboxamido group may be prepared from compounds of formula (I)wherein R³ represents a group containing R⁶ which is substituted by acyano group, by means of reaction with hydrogen peroxide and potassiumcarbonate in dimethyl sulphoxide.

As another example of the interconversion process, compounds of formula(I) wherein R³ represents a group containing R⁶ which is substituted bya cyano group may be prepared from compounds of formula (I) wherein R³represents a group containing R⁶ which is substituted by a bromine atom,by means of reaction with zinc cyanide in the presence oftetrakis(triphenylphosphine) palladium(0) in an inert solvent, such asdimethylformamide, at a temperature at about 100° C.

As another example of the interconversion process, compounds of formula(I) wherein R¹ is substituted by fluorine on a carbon atom thereof alphato the attachment of R¹ to Z¹ as sulphur, may be prepared by reactingxenon difluoride with corresponding compound of formula (I) wherein saidalpha-carbon atoms carry hydrogen atoms instead of said fluorine atoms.The reaction is conveniently carried out in a solvent, such asdichloromethane, in the presence of a molecular sieve, and in an inertatmosphere, at a low temperature, such as at about 0° C.

As another example of the interconversion process, compounds of formula(I) wherein R¹ is a difluoromethyl group and Z¹ is an oxygen or sulphuratom, may be prepared by reacting a compound of formula (I) wherein R¹is a hydrogen atom and Z¹ is an oxygen or sulphur atom, with HCBrF₂ inthe presence of a strong base in an inert solvent.

As another example, compounds of formula (I) wherein R³ represents agroup containing R⁶ which is a heteroaryl group containing one or morenitrogen ring atoms but carrying no halogen substituents may be preparedby the reduction of the corresponding compounds of formula (I) whereinR³ represents a group containing R⁶ which does carry one or more halo,such as chloro, substituents, for example by means of ammonium formatein the presence of a palladium catalyst.

As another example, compounds of formula (I) wherein the moiety R³contains a cis alkenyl group may be prepared by the action ofultraviolet radiation upon the trans-isomer.

As another example of the interconversion process, compounds of formula(I) wherein R³ contains a cis —N═N— linkage may be prepared by theaction of ultraviolet radiation upon their trans-isomers.

As another example of the interconversion process, compounds of formula(I) containing sulphoxide linkages may be prepared by the oxidation ofcorresponding compounds containing —S-linkages. For example, theoxidation may conveniently be carried out by means of reaction with aperoxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inertsolvent, e.g. dichloromethane, preferably at or near room temperature,or alternatively by means of potassium hydrogen peroxomonosulphate in amedium such as aqueous methanol, buffered to about pH5, at temperaturesbetween about 0° C. and room temperature. This latter method ispreferred for compounds containing an acid-labile group.

As another example of the interconversion process, compounds of formula(I) containing sulphone linkages may be prepared by the oxidation ofcorresponding compounds containing —S— or sulphoxide linkages. Forexample, the oxidation may conveniently be carried out by means ofreaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably inan inert solvent, e.g. dichloromethane, preferably at or near roomtemperature.

As another example of the interconversion process, compounds of formula(I) wherein R³ represents a group containing a —CSCH₂- linkage may beprepared from compounds of formula (I) wherein R³ represents a groupcontaining a —COCH₂- linkage by reaction with phosphorus pentasulphideor 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide,preferably in a solvent such as pyridine or toluene, and preferably at atemperature from 0° C. to the reflux temperature.

As another example of the interconversion process, compounds of formula(I) containing a hydroxymethyl group may be prepared by the reduction ofthe corresponding compounds of formula (I) containing an aryloxycarbonylor, particularly, alkoxycarbonyl group, preferably by means of reactionwith an alkali metal borohydride, preferably in an inert solvent, e.g.tetrahydrofuran, and preferably at or near room temperature.

As another example of the interconversion process, compounds of formula(Ib) in which R² is hydrogen and A¹ is a direct bond may be prepared byheating compounds of formula (Ib) in which the group R² is abutyloxycarbonyl group and A¹ is a direct bond.

According to a further feature of the invention, acid addition salts ofthe compounds of this invention may be prepared by reaction of the freebase with the appropriate acid, by the application or adaptation ofknown methods. For example, the acid addition salts of the compounds ofthis invention may be prepared either by dissolving the free base inwater or aqueous alcohol solution or other suitable solvents containingthe appropriate acid and isolating the salt by evaporating the solution,or by reacting the free base and acid in an organic solvent, in whichcase the salt separates directly or can be obtained by concentration ofthe solution.

The acid addition salts of the compounds of this invention can beregenerated from the salts by the application or adaptation of knownmethods. For example, parent compounds of the invention can beregenerated from their acid addition salts by treatment with an alkali,e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.

According to a further feature of the invention, base addition salts ofthe compounds of this invention may be prepared by reaction of the freeacid with the appropriate base, by the application or adaptation ofknown methods. For example, the base addition salts of the compounds ofthis invention may be prepared either by dissolving the free acid inwater or aqueous alcohol solution or other suitable solvents containingthe appropriate base and isolating the salt by evaporating the solution,or by reacting the free acid and base in an organic solvent, in whichcase the salt separates directly or can be obtained by concentration ofthe solution.

Compounds of this invention can be regenerated from their base additionsalts by the application or adaptation of known methods. For example,parent compounds of the invention can be regenerated from their baseaddition salts by treatment with an acid, e.g. hydrochloric acid.

Compounds of the present invention may be conveniently prepared, orformed during the process of the invention, as solvates (e.g. hydrates).Hydrates of compounds of the present invention may be convenientlyprepared by recrystallisation from water.

The starting materials and intermediates may be prepared by theapplication or adaptation of known methods, for example methods asdescribed in the Reference Examples or their obvious chemicalequivalents.

Intermediates of formula (II, T¹-C(═O)X⁶) wherein T¹ is as hereinbeforedefined and X⁶ represents an O-benzotriazol-1-yl group may be preparedby reaction of compounds of formula (1):T¹-CO₂H  (1)wherein T¹ is as hereinbefore defined, withO-benzotriazol-1-yl-N,N,N′,N′,-bis(tetramethylene)uroniumtetrafluoroborate in an inert solvent, for example dichloromethane, at atemperature at about ambient temperature.

Intermediates of formula (II, T¹-C(═O)X⁶) wherein T¹ is as hereinbeforedefined and X⁶ represents an azido group may be prepared from compoundsof formula (1) wherein T¹ is as hereinbefore defined by the applicationor adaptation of known methods for the preparation of acid azides fromcarboxylic acids. For example, the reaction may be carried out by meansof diphenylphosphoryl azide in the presence of triethylamine indimethylformamide.

Intermediates of formula (II, T¹-C(═O)X⁶) wherein T¹ is as hereinbeforedefined and X⁶ represents a halogen atom may be prepared from compoundsof the general formula (1) wherein T¹ is as hereinbefore defined, by theapplication or adaptation of known methods for the preparation of acidhalides from carboxylic acids. For example, when X⁶ represents achlorine atom, the reaction may be carried out by means of thionylchloride or, preferably, oxalyl chloride, optionally in the presence ofa small amount of dimethylformamide.

Compounds of formula (1, T¹-CO₂H), wherein T¹ is as hereinbefore definedmay be prepared by hydrolysis of compounds of formula (IV, T¹-CO₂R⁴⁹)wherein T¹ and R⁴⁹ are as hereinbefore defined. The hydrolysis may forexample be carried out by reaction with a base, such as an alkali metalhydroxide, e.g. sodium or lithium hydroxide, or an alkali metalcarbonate, e.g. potassium carbonate, in the presence of water, in analcohol such as methanol and at a temperature from about ambient toabout reflux, followed by reaction with an aqueous acid such as dilutehydrochloric acid.

Intermediates of the general formula (III, R⁶NHR⁴⁸)

wherein R⁶ is as hereinbefore described, including N-oxides ofheteroaryl groups, and R⁴⁸ represents an alkanoyl group, e.g. acetylgroup may be prepared for example, by the application or adaptation ofknown methods for the acylation or aromatic amines.

Intermediates of formula (IV) represented by the formula (2):

wherein

R⁵³ represents CO₂R⁴⁹ (in which R⁴⁹ is as hereinbefore defined), and R¹,A¹, Q¹ and Z¹ are as hereinbefore defined (with the proviso that when A¹is a direct bond then R² is alkyl, cycloalkyl, aryl, or heteroaryl), maybe prepared by reaction of compounds of formula (3):

wherein R¹, R², A¹, Q¹ and Z¹ are as hereinbefore described (with theproviso that when A¹ is a direct bond then R² is alkyl, cycloalkyl,aryl, or heteroaryl), and R⁵³ represents —CO₂R⁴⁹ (in which R⁴⁹ is ashereinbefore defined), with sodium hypochlorite in the presence of anaqueous acid such as dilute hydrochloric acid, in an alcohol, such asmethanol, and at a temperature at about ambient temperature, followed bytreatment of the resultant chloroimine with an alkali metal carbonate,such as sodium carbonate, at a temperature of about reflux temperature.

Intermediates of formula (VIII) represented by the formula (2), wherein

R⁵³ represents —C(═O)—R⁸ (in which R⁸ is optionally substituted alkyl),and R¹, R² and A¹ are as hereinbefore defined, Q¹ is CH and Z¹ is anoxygen atom (with the proviso that when A¹ is a direct bond then R² isalkyl, cycloalkyl, aryl, or heteroaryl), may be similarly prepared fromcompounds of formula (3) wherein R¹, R² and A¹ are as hereinbeforedefined, R⁵³ is a group —C(═O)—R⁸ (in which R⁸ is optionally substitutedalkyl), Q¹ is a CH linkage and Z¹ is an oxygen atom (with the provisothat when A¹ is a direct bond then R² is alkyl, cycloalkyl, aryl, orheteroaryl).

Intermediates of formula (X) represented by the formula (2), wherein

R⁵³ represents —C(═O)—R¹⁰ (in which R¹⁰ is a group —(CH₂)_(p)R⁶ where R⁶and n are as hereinbefore defined); R¹, R² and A¹ are as hereinbeforedefined; Q¹ is CH and Z¹ is an oxygen atom (with the proviso that whenA¹ is a direct bond then R² is alkyl, cycloalkyl, aryl, or heteroaryl),may be similarly prepared from compounds of formula (3) wherein R¹, R²and A¹ are as hereinbefore defined, R⁵³ is a group —C(═O)—R¹⁰ (in whichR¹⁰ is a group —(CH₂)_(p)R⁶ in which R⁶ and n are as hereinbeforedefined), Q¹ is a CH linkage and Z¹ is an oxygen atom (with the provisothat when A¹ is a direct bond then R² is alkyl, cycloalkyl, aryl, orheteroaryl).

Intermediates of formula (XVIII) represented by the formula (2), wherein

R⁵³ represents a halogen atom, Q¹ is a CH linkage, Z¹ is an oxygen atomand R¹, R² and A¹ are as hereinbefore defined, (with the proviso thatwhen A¹ is a direct bond then R² is alkyl, cycloalkyl, aryl, orheteroaryl), may be similarly prepared from compounds of formula (3)wherein

R⁵³ is a halogen atom, Q¹ is a CH linkage, Z¹ is an oxygen atom and R¹,R² and A¹ are as hereinbefore defined (with the proviso that when A¹ isa direct bond then R² is alkyl, cycloalkyl, aryl, or heteroaryl).

-   -   Compounds of formula (18) represented by the formula (2),        wherein R⁵³ is a nitro group and        R¹, R², A¹, Q¹ and Z¹ are as hereinbefore defined (with the        proviso that when A¹ is a direct bond then R² is alkyl,        cycloalkyl, aryl, or heteroaryl), may be similarly prepared from        compounds of formula (3) wherein R⁵³ is a nitro group and R¹,        R², A¹, Q¹ and Z¹ are as hereinbefore defined (with the proviso        that when A¹ is a direct bond then R² is alkyl, cycloalkyl,        aryl, or heteroaryl).

Compounds of formula (19), represented by the formula (2), wherein R⁵³is a methyl group and

R¹, R², A¹, Q¹ and Z¹ are as hereinbefore defined (with the proviso thatwhen A¹ is a direct bond then R² is alkyl, cycloalkyl, aryl, orheteroaryl), may be similarly prepared from compounds of formula (3)wherein R⁵³ is a methyl group and R¹, R², A¹, Q¹ and Z¹ are ashereinbefore defined (with the proviso that when A¹ is a direct bondthen R² is alkyl, cycloalkyl, aryl, or heteroaryl).

Compounds of formula (3), wherein R¹, R², R⁵³, A¹, Q¹ and Z¹ are ashereinbefore defined (with the proviso that when A¹ is a direct bondthen R² is alkyl, cycloalkyl, aryl, or heteroaryl), may be prepared byreaction of compounds of formula (4):

wherein R¹, R⁵³, Q¹ and Z¹ are as hereinbefore defined, with compoundsof formula R²A¹C≡N, wherein R² and A¹ are as hereinbefore defined (withthe proviso that when A¹ is a direct bond then R² is alkyl, cycloalkyl,aryl, or heteroaryl), in the presence of an acid catalyst, such as4-toluenesulphonic acid, at a temperature up to about 180° C.

Intermediates of formula (XXXXV) wherein R¹, R², R³, A¹, Q¹ and Z¹ areas hereinbefore defined (with the proviso that when A¹ is a direct bondthen R² is alkyl, cycloalkyl, aryl, or heteroaryl), may be similarlyprepared by reaction of compounds of formula (4) wherein R¹, Q¹ and Z¹are as hereinbefore defined and R⁵³ is a group —R³, with compounds offormula R²A¹C≡N, wherein R² and A¹ are as hereinbefore defined (with theproviso that when A¹ is a direct bond then R² is alkyl, cycloalkyl,aryl, or heteroaryl), in the presence of an acid catalyst, such as4-toluenesulphonic acid, at a temperature up to about 180° C.

Compounds of formula (4) wherein R¹ is as hereinbefore defined, R⁵³represents a group —CO₂R⁴⁹ in which R⁴⁹ is as hereinbefore defined, Z¹represents an oxygen atom and Q¹ represents a nitrogen atom, may beprepared by reaction of compounds of formula (5):

wherein R¹ and R⁴⁹ are as hereinbefore defined, with ammonium hydroxidein the presence of sulphur dioxide according to the procedure of H.King, J. Chem. Soc, 1946, page 523.

Compounds of formula (4) wherein R¹ and R⁵³ are as hereinbefore defined,Z¹ represents an oxygen atom or a direct bond and Q¹ represents a CH ora CF linkage, may be prepared by reduction of compounds of formula (6):

wherein R¹ and R⁵³ are as hereinbefore defined, Z¹ represents an oxygenatom or a direct bond and Q¹ represents a CH or a CF linkage. Thereduction may conveniently be carried out using hydrogen in the presenceof a suitable metal catalyst, e.g. platinum or palladium optionallysupported on an inert carrier such as carbon, preferably in a solventsuch as methanol or ethanol. Alternatively the reduction may be carriedout ammonium chloride and iron, in an aqueous/organic solvent mixture,for example aqueous methanol, at a temperature at about reflux.

Compounds of formula (6), wherein R¹ and R⁵³ are as hereinbeforedefined, Z¹ represents an oxygen atom or a direct bond and Q¹ representsa CH or a CF linkage, may be prepared by nitration of compounds offormula (7):

wherein R¹ and R⁵³ are as hereinbefore defined, Z¹ represents an oxygenatom or a direct bond and Q¹ represents a CH or a CF linkage, withfuming nitric acid at a temperature from about ambient temperature toabout 60° C., and separation of the required nitro-isomer (6).

Compounds of formula (6), wherein R¹ is C₁₋₄alkyl, R⁵³ is a bromineatom, Q¹ represents a CH linkage and Z¹ represents an oxygen atom, maybe prepared by bromination of the appropriate2-(C₁₋₄alkoxy)-nitrobenzene according to the procedure of S. Kajigaeshiet. al. J. C. S. Perkin Trans. I, 1990, page 897.

Compounds of formula (6), wherein R¹ is C₁₋₄alkyl, R⁵³ is an iodineatom, Q¹ represents a CH linkage and Z¹ represents an oxygen atom, maybe prepared by thallation of the appropriate 2-(C₁₋₄alkoxy)-nitrobenzenewith thallium trifluoroacetate in trifluoroacetic acid followed byiodination with aqueous potassium iodide according to the procedure ofA. Mckillop et. al. Tetrahedron. Letters, 1969, page 2427.

Compounds of formula (4), wherein R¹ is as hereinbefore defined and R⁵³is a group —SO₂NR²¹R²² in which R²¹ and R²² are as hereinbeforedescribed, Q¹ is a CH linkage and Z¹ is an oxygen atom, may be preparedfrom reaction of 3-acetamido-4-methoxybenzene sulphonyl chloride(prepared according to the procedure of B. M. Culbertson, J. Chem. Soc.,1968, page 992) with amines of formula R²¹R²²NH wherein R²¹ and R²² areas hereinbefore described and subsequent treatment with sodiumhydroxide.

Compounds of formula (7), wherein R¹ is as hereinbefore defined, R⁵³represents —CO₂R⁴⁹ (in which R⁴⁹ is as hereinbefore defined), Z¹represents an oxygen atom and Q¹ represents a CF linkage may be preparedby reaction of compounds of formula (8):

wherein R¹ is as hereinbefore defined, with the appropriate C₁₋₅alkylalcohol, in the presence of hydrogen chloride at a temperature up toabout reflux.

Compounds of formula (8), wherein R¹ is as hereinbefore defined, may beprepared by reaction of 4-hydroxy-2-fluorobenzonitrile with compounds ofthe formula (9):R¹X¹²  (9)wherein R¹ is as hereinbefore described and X¹² is a bromine or chlorineatom, or a triflate group. The reaction may be carried out in thepresence of an alkali metal carbonate, such as potassium carbonate, inan inert solvent such as dimethylformamide, and at a temperature fromabout room temperature to about 80° C.

Intermediates of formula (2), wherein

R⁵³ represents —CO₂R⁴⁹ (in which R⁴⁹ is as hereinbefore defined), A¹ isa direct bond, R² is an alkoxy group, and R¹, Q¹ and Z¹ are ashereinbefore defined, may be prepared by reaction of compounds offormula (10):

wherein R¹, R⁴⁹, Q¹ and Z¹ are as hereinbefore described, with compoundsof formula (XXXXVIII), wherein R⁴⁹ is as hereinbefore defined. Thereaction is carried out in acetic acid at a temperature up to aboutreflux temperature.

Intermediates of formula (2), wherein

R⁵³ represents —CO₂R⁴⁹ (in which R⁴⁹ is as hereinbefore defined), andR¹, A¹, Q¹ and Z¹ are as hereinbefore defined (with the proviso thatwhen A¹ is a direct bond then R² is alkyl, cycloalkyl, aryl, orheteroaryl), may be prepared by reaction of compounds of formula (10),wherein R¹, R⁴⁹, Q¹ and Z¹ are as hereinbefore described, with compoundsof formula (XXXXVII, R²A¹C(═O)X¹⁰), wherein R² and A¹ are ashereinbefore defined (with the proviso that when A¹ is a direct bondthen R² is alkyl, cycloalkyl, aryl, or heteroaryl), and X¹⁰ represents ahydroxy group or a halogen atom, preferably a chlorine atom. When X¹⁰represents a hydroxy group the reaction is preferably carried out in thehydrochloric acid at a temperature at about 125° C. When X¹⁰ representsa chlorine atom the reaction is preferably carried out in an inertsolvent, such as dichloromethane, optionally in the presence oftriethylamine and at a temperature from about 0° C. to about ambienttemperature, followed by reaction of the product with acetic acid at atemperature at about reflux.

Compounds of formula (10), wherein R¹, R⁴⁹ and Z¹ are as hereinbeforedefined and Q¹ represents a CH linkage, may be prepared by reduction ofcompounds of formula (11):

wherein R¹, R⁴⁹ and Z¹ are as hereinbefore described. The reduction maybe carried out using hydrogen in the presence of a suitable metalcatalyst, e.g. platinum or palladium optionally supported on an inertcarrier such as carbon, preferably in a solvent such as methanol orethanol.

Compounds of formula (11) wherein R¹, R⁴⁹ and Z¹ are as hereinbeforedescribed may be prepared by conversion of the carboxy group incompounds of formula (12):

wherein R¹, R⁴⁹ and Z¹ are as hereinbefore described, into an aminogroup. The process involves initial reaction with thionyl chloride, inan inert solvent such as toluene, in the presence of dimethylformamideand at a temperature at about reflux, to form the corresponding acidchloride. The acid chloride is then reacted with a sodium azide inaqueous acetone at a temperature from about 0° C. to about ambienttemperature to form the corresponding acid azide, which is heated in anaqueous alcohol, such as t-butanol, at a temperature at about reflux.

Compounds of formula (12) wherein R¹, R⁴⁹ and Z¹ are as hereinbeforedescribed may be prepared by esterification of the correspondingphthalic acid of formula (13):

wherein R¹ and Z¹ are as hereinbefore described with the appropriateC₁₋₅alkyl alcohol.

Compounds of formula (13) wherein R¹ and Z¹ are as hereinbeforedescribed may be prepared by nitration of the corresponding phthalicacid of formula (14):

wherein R¹ and Z¹ are as hereinbefore described, with fuming nitric acidat a temperature from about ambient temperature to about 60° C.

Intermediates of formula (2), wherein

(in which R⁵ represents a C₁₋₄straight- or branched-chain alkyl, anarylC₁₋₄alkyl or a heteroarylC₁₋₄alkyl group), R⁵³ represents —CO₂R⁴⁹(in which R⁴⁹ is as hereinbefore defined), and R¹, R², A¹, Q¹ and Z¹ areas hereinbefore defined, may be prepared by reaction of compounds offormula (2), wherein

R⁵³ represents —CO₂R⁴⁹ (in which R⁴⁹ is as hereinbefore defined), andR¹, R², A¹, Q¹ and Z¹ are as hereinbefore defined, with a C₁₋₄straight-or branched-chain alkyl halide or a arylC₁₋₄alkyl halide or aheteroarylC₁₋₄alkyl halide respectively. The alkylation may for examplebe carried out in the presence of a base, such as an alkali metalhydride, e.g. sodium hydride, in dimethylformamide at a temperature fromabout 0° C. to about ambient temperature.

Intermediates of formula (IV) or (XXXIII) represented by formula (15):

wherein R¹, R², A¹, and Z¹ are as hereinbefore defined, R⁵³ represents—CO₂R⁴⁹ (in which R⁴⁹ is as hereinbefore defined) or OH, and Q is CH orN, may be prepared for example by the application or adaptation of knownmethods for the substitution of the imino (NH) group in indoles orindazines of general formula (16):

wherein R¹ and Z¹ are as defined previously, R⁵³ represents —CO₂R⁴⁹ (inwhich R⁴⁹ is as hereinbefore defined), and Q is CH or N.

Intermediates of formula (16) wherein R¹ and Z¹ are as definedpreviously, R⁵³ represents CO₂R⁴⁹ (in which R⁴⁹ is as hereinbeforedefined) and Q is N may be prepared from compounds of general formula(17), wherein R¹ and Z¹ are as hereinbefore defined, as shown in Scheme(I):

Scheme (I)

Reactio conditions:

-   (i) treatment with boron tribromide in an inert solvent, such as    dichloromethane, at a temperature from about 0° C. to about reflux    temperature.-   (ii) treatment with N-phenyltrifluoromethane sulphonimide in the    presence of a suitable base such as sodium hydride in an inert    solvent, such as tetrahydrofuran, at a temperature at about 50° C.-   (iii) treatment with carbon monoxide in the presence of palladium    acetate, diphenylphosphine ferrocene, triethylamine and methanol.-   (iv) treatment with a suitable base, e.g. an alkali metal carbonate,    such as potassium carbonate, in a mixture of an alcohol, such as    methanol, and water at a temperature up to about reflux temperature.-   (v) treatment with the appropriate alcohol R⁴⁹—OH in the presence of    hydrogen chloride at room temperature.

Compounds of general formula (17), wherein R¹ is methyl and Z¹ is adirect bond may be prepared by treatment of2-fluoro-4-methoxyacetophenone with hydrazine at a temperature up toabout reflux temperature.

Compounds of formula (16) wherein R¹ and Z¹ are as defined previously,R⁵³ represents OH and Q is N may be prepared from compounds of generalformula (17), wherein R¹ and Z¹ are as hereinbefore defined, as shown inthe first step of Scheme (I).

Intermediates of formula (VI), wherein T¹ and R⁶ are as hereinbeforedefined, may be prepared by reaction of compounds of formula (XXVI)wherein T¹ is as hereinbefore defined with compounds of general formula(V), wherein R⁶ is as hereinbefore described, in the presence of astrong base such as lithium diisopropylamine, in an inert solvent, forexample an ether such as tetrahydrofuran, preferably at a temperaturefrom −65° C. to 0° C.

Intermediates of formula (VIII), wherein T¹ is as hereinbefore defined,and R₈ is hydrogen [i.e. T¹-C(═O)H, compounds of formula (XXVI)] may beprepared by oxidation of compounds of formula (XXIX) with manganesedioxide in an inert solvent, such as dichloromethane or toluene (or amixture of both), and at a temperature from about room temperature toabout 85° C.

Intermediates of formula (XIV), wherein T¹, R¹⁰, R¹¹ and R¹² are ashereinbefore defined, may be prepared by reaction of compounds offormula (X) wherein T¹ and R¹⁰ are as hereinbefore defined, with anorganometallic reagent R¹¹ (R¹²)CHM [where M is a metal atom, forexample a lithium atom] in a solvent such as an ether (e.g.tetrahydrofuran) at a low temperature, e.g. about −78° C. to ambienttemperature. Reagents R¹¹(R¹²)CHM are either known compounds or may beprepared, preferably in situ during the above process, by reaction of acompound AlkCH₂M or [Alk]₂NM [where Alk is an alkyl group such asn-propyl or i-propyl] with a compound R¹¹CH₂R¹² using the just mentionedconditions. Intermediates of formula (XV,T¹-C(R⁸)(OH)CH(R⁹)(CH₂)_(p)R⁶), wherein T¹, R⁶, R⁸ and R⁹ are ashereinbefore defined, may be similarly prepared by reaction of compoundsof formula (VIII) wherein T¹ and R⁸ are as hereinbefore defined, with anorganometallic reagent R⁶(CH₂)_(p)(R⁹)CHM [where M is a metal atom, forexample a lithium atom].

Intermediates of formula (XVI, T¹-B(OH)₂), wherein T¹ is as hereinbeforedefined, may be prepared by reaction of compounds of formula (XVIII),wherein T¹ is as hereinbefore defined, with n-butyl lithium, in an inertsolvent such as tetrahydrofuran, at a temperature about −78° C.,followed by reaction with a trialkylborate, such as triethyl borate, andsubsequent hydrolysis with a dilute mineral acid such as hydrochloricacid.

Intermediates of formula (XX, T¹-NH₂), wherein T¹ is as hereinbeforedefined, may be prepared by hydrogenation of compounds of formula (18):T¹-NO₂  (18)wherein T¹ is as hereinbefore defined. The hydrogenation may be carriedout using hydrogen in the presence of a suitable metal catalyst, e.g.palladium optionally supported on an inert carrier such as carbon,preferably in a solvent such as methanol or ethanol.

Intermediates of formula (XXII, T¹-C(═NOH)CH₃), wherein T¹ is ashereinbefore defined, may be prepared by reaction of compounds offormula (VIII) wherein T¹ is as hereinbefore described and R⁸ is methyl,with hydroxylamine hydrochloride in the presence of pyridine, in aninert solvent, such as dichloromethane, at a temperature at about roomtemperature.

Intermediates of formula (XXV, T¹-CH₂CH(OH)R⁶), wherein T¹ and R⁶ are ashereinbefore defined, may be prepared by reaction of compounds offormula (19):T¹-CH₃  (19)wherein T¹ is as hereinbefore described, with a strong base such aslithium diisopropylamide, in an inert solvent, such as tetrahydrofuranat a temperature at about −78° C. followed by reaction of with compoundsof formula (XXXII, R⁶CHO) wherein R⁶ is as hereinbefore described.

Intermediates of formula (XXVII, T¹-CH₂X⁷), wherein T¹ is ashereinbefore described and X⁷ is a bromine atom, may be prepared bybromination of compounds of formula (19), wherein T¹ is as hereinbeforedescribed, with N-bromosuccinimide, optionally in the presence of acatalyst, such as benzoyl peroxide, in an inert solvent such asdichloromethane and at a temperature at about room temperature.

Alternatively intermediates of formula (XXVII, T¹-CH₂X⁷), wherein T¹ isas hereinbefore described and X⁷ is a bromine atom, may be prepared byreaction of compounds of formula (XXIX, T¹-CH₂OH), wherein T¹ is ashereinbefore described, with N-bromosuccinimide, optionally in thepresence of a catalyst, such as benzoyl peroxide, in an inert solventsuch as dichloromethane and at a temperature at about room temperature.

Intermediates of formula (XXIX, T¹-CH₂OH), wherein T¹ is as hereinbeforedescribed may be prepared by reduction of compounds of formula (IV,T¹-CO₂R⁴⁹) wherein T¹ and R⁴⁹ are as hereinbefore described. Thereduction may conveniently be carried out with diisobutylaluminiumhydride in an inert solvent, such as tetrahydrofuran, at a temperaturefrom about −78° C. to about room temperature. The reduction may also becarried out with lithium aluminium hydride in an inert solvent, such asan ether, for example diethyl ether, at a temperature from about roomtemperature to about reflux.

Intermediates of formula (XXXI) wherein T¹ is as hereinbefore definedmay be prepared from compounds of the general formula (20):T¹-CHF₂  (20)wherein T¹ is as hereinbefore defined, by reaction with bromine incarbon tetrachloride and ultraviolet radiation, at a temperature fromabout ambient to about reflux.

Compounds of formula (20) wherein T¹ is as hereinbefore defined may beprepared by the action of sulphur tetrafluoride and hydrofluoric acid oncompounds of formula (XXVI) wherein T¹ is as hereinbefore defined,optionally in the presence of pyridine, at a temperature from about roomtemperature to about 125° C., or alternatively by the action ofdiethylaminosulphur trifluoride, preferably in an inert solvent, such asdichloromethane, preferably at a temperature from about 0° C. to aboutroom temperature.

Intermediates of formula (XXXVII, T¹-N₂ ⁺BF₄ ⁻), wherein T¹ is ashereinbefore defined may be prepared by diazotisation of compounds offormula (XX) with sodium nitrite in the presence of hydrochloric acid,followed by treatment with sodium tetrafluoroborate.

Intermediates of formula (XXXX, T¹-SO₂Cl), wherein T¹ is as hereinbeforedefined may be prepared by reaction of compounds of formula (XVIII,T¹-X⁷), wherein T¹ is as hereinbefore defined and X⁷ is a bromine atomwith butyllithium in tetrahydrofuran at a temperature at about −70° C.followed by treatment with sulphur dioxide at about the same temperatureand subsequent reaction of the resulting lithium sulphinate salt withsulphuryl chloride in an inert solvent such as dichloromethane at atemperature at about 0° C.

Intermediates of formula (XXXXII, T¹-C(═O)CO₂H), wherein T¹ is ashereinbefore defined may be prepared by the oxidation of compounds offormula (VIII, T¹-C(═O)R₈) wherein T¹ is as hereinbefore described andR₈ is methyl, by reaction with selenium dioxide in the presence ofpyridine, using mild conditions, e.g. in a solvent such as ethanol, ator below room temperature.

Intermediates of the general formula (XXXXIII) wherein T¹ is ashereinbefore defined may be prepared by treatment of compounds offormula (XX) wherein T¹ is as hereinbefore defined with the phosgeneequivalent (ClC(═O)OCCl₃) in an inert solvent such as dioxan at atemperature at about 60° C.

Intermediates of formulae (XXXXIX), (L) and (LII) wherein R¹, R³,

Q¹ and Z¹ are as hereinbefore described, may be prepared by theapplication or adaptation of methods for the reactions ofo-arylenediamines described in Comprehensive Heterocyclic Chemistry,page 470.

Intermediates of formula (LIV, T¹-C(CN)[(CH₂)₂CO₂R⁵²]₂), wherein T¹ isas hereinbefore described, may be prepared by reaction of compounds offormula (21):T¹-CH₂CN  (21)wherein T¹ is as hereinbefore described, with methyl (or ethyl) acrylatein methanol, in the presence of a suitable catalyst, such as Triton-B,and at reflux temperature.

Compounds of formula (21), wherein T¹ is as hereinbefore described, maybe prepared by reaction of compounds of formula (XXVII), wherein T¹ isas hereinbefore described and X⁷ represents a chlorine atom, with sodiumcyanide in dimethylformamide.

Intermediates of the general formula (LV, T¹-CH═CH—CO₂H) wherein T¹ isas hereinbefore described may be prepared by reaction of compounds offormula (XXVI, T¹-CHO) with malonic acid in the presence of piperidinein a solvent such as pyridine at a temperature up to about reflux.

Intermediates of the general formula (LVII), wherein T¹ is ashereinbefore described may be prepared by reaction of compounds offormula (22):T¹-CH═CHCO₂R⁴⁹  (22)wherein T¹ and R⁴⁹ are as hereinbefore described, with an nitromethanein the presence of tetramethylguanidine at a temperature at about 65° C.

Compounds of formula (22), wherein T¹ and R⁴⁹ are as hereinbeforedescribed may be prepared by reaction of compounds of formula (XXVI)with a carboalkoxymethylene triphenylphosphorane, e.g.carbomethoxymethylene triphenylphosphorane, in an inert solvent, such astoluene, and at a temperature from about room temperature to about 80°C.

Intermediates of formula (LVIII), wherein T¹ is as hereinbeforedescribed, may be prepared from compounds of formula (23):T¹-CH(NHCO₂Me)CH₂CH═CH₂  (23)wherein T¹ is as hereinbefore described, following hydroboration of thedouble bond with for example diisoamylborane in tetrahydrofuran at 0° C.and subsequent treatment with sodium hydroxide and hydrogen peroxide at0° C.

Compounds of formula (23), wherein T¹ is as hereinbefore described, maybe prepared by reaction of compounds of formula (24):T¹-CH(CO₂H)CH₂CH═CH₂  (24)wherein T¹ is as hereinbefore described, with thionyl chloride, at roomtemperature, followed by reaction of the resulting acid chloride withsodium azide in acetone at 0° C. to room temperature then thermolysis byrefluxing in an inert solvent such as benzene to furnish the isocyanatewhich may be converted to the required urethane by refluxing inmethanol.

Compounds of formula (24, T¹-CH(CO₂H)CH₂CH═CH₂), wherein T¹ is ashereinbefore described, may be prepared by alkylation of the aciddianion (obtained following treatment with two equivalents of lithiumdiisopropylamine in tetrahydrofuran) derived from compounds of formula(25):T¹-CH₂CO₂H  (25)wherein T¹ is as hereinbefore described, with allyl bromide.

Intermediates of formula (Iz) wherein T¹ is as hereinbefore describedand the moiety R³ represents a

group in which R⁵² is a methyl or ethyl group, may be prepared fromcompounds of formula (XXVI) by reaction with hydroxylamine hydrochloridein the presence of pyridine, followed by treatment of the so formedoxime with N-chlorosuccinimide and pyridine in an inert solvent, such asdichloromethane, and subsequent reaction of the chloroamidoxime withmethyl or ethyl acrylate in the presence of triethylamine.

Intermediates of formula (LIX), wherein R¹, R², A¹, Q¹ and Z¹ are ashereinbefore defined, R³ represents a —O—CH₂—R⁶ group where R⁶ is ashereinbefore defined, and {circumflex over (P)} is a suitable protectinggroup, for example a 2-trimethylsilanyl-ethoxymethyl group, may beprepared by reaction of compounds of formula (26):

wherein R¹, R², A¹, Q¹ and Z¹ are as hereinbefore defined, and {circleover (P)} is a suitable protecting group, for example a2-trimethylsilanyl-ethoxymethyl group, with compounds of formula (27):R⁶CH₂OH  (27)wherein R⁶ is as hereinbefore defined, in the presence of a dialkylazodicarboxylate, such as diethyl azodicarboxylate, andtriphenylphosphine, preferably in a dry ethereal solvent, e.g. diethylether or tetrahydrofuran, preferably at or near room temperature.

Compounds of formula (26) wherein R¹, R², A¹, Q¹ and Z¹ are ashereinbefore defined, and {circumflex over (P)} is a suitable protectinggroup, for example a 2-trimethylsilanyl-ethoxymethyl group, may beprepared by reaction of compounds of formula (28):

wherein R¹, R², A¹, Q¹ and Z¹ are as hereinbefore defined, and {circleover (P)} is a suitable protecting group, for example a2-trimethylsilanyl-ethoxymethyl group, with m-chloroperbenzoic acid inan inert solvent such dichloromethane and at a temperature from about 0°C. to about room temperature followed by treatment with sodium hydrogencarbonate.

Intermediates of formula (XXXIII), wherein T¹ is as hereinbeforedefined, may be similarly prepared by reaction of compounds of formula(XXVI), wherein T¹ is as hereinbefore defined, with m-chloroperbenzoicacid.

Compounds of formula (28) wherein R¹, R², A¹, Q¹ and Z¹ are ashereinbefore defined, and {circle over (P)} is a2-trimethylsilanyl-ethoxymethyl group, may be prepared by reaction ofcompounds of formula (2), wherein

R⁵³ represents a formyl group, and R¹, R², A¹, Q¹ and Z¹ are ashereinbefore defined, with 2-(trimethylsilyl)ethoxymethyl chloride inthe presence of sodium hydride, in an inert solvent such asdimethylformamide, and at a temperature at about room temperature.

Compounds of formula (XXXIV) wherein R⁶ is as hereinbefore defined andX⁸ is hydroxy may be prepared by reduction of compounds of formula(XXXII) wherein R⁶ is as hereinbefore defined. The reduction mayconveniently be carried out with sodium borohydride in an alcohol suchas ethanol at a temperature at about room temperature.

Compounds of formula (XXXII) wherein R⁶ is heteroaryl, such as asubstituted pyridyl, for example 3,5-dimethylpyridyl, may be prepared byreaction of compounds of formula (29):R⁶Br  (29)wherein R⁶ is heteroaryl, such as a substituted pyridyl, for example3,5-dimethylpyridyl, with butyl lithium in an inert solvent, such asdiethyl ether, at −78° C., and subsequent treatment of the resultinganion with dimethylformamide.

Compounds of formula (29) wherein R⁶ is 3,5-dimethylpyridyl, may beprepared by reaction of 4-nitro-3,5-dimethylpyridine-N-oxide withphosphorous tribromide in a similar manner to the procedures describedin J. Chem. Soc., 1956, page 771.

Intermediates of formula (IV) represented by formula (30):

wherein R¹, R², A¹, and Z¹ are as hereinbefore defined, R⁵³ is CO₂R⁴⁹(in which R⁴⁹ is as hereinbefore defined), may be prepared for exampleby reaction of compounds of formula (4), wherein R¹ and Z¹ are ashereinbefore defined, R⁵³ is CO₂R⁴⁹ (in which R⁴⁹ is as hereinbeforedefined) and Q is CH, with compounds of formula (31):R²A¹-CH═CH—CHO  (31)wherein R² and A¹ are as hereinbefore defined, in the presence ofp-chloranil in a alcohol, such as butanol, and at a temperature at aboutreflux temperature.

Intermediates of formula (IV) represented by formula (32):

wherein R¹ is hydrogen, R² is alkyl, aryl or heteroaryl, R⁵³ is CO₂R⁴⁹(in which R⁴⁹ is as hereinbefore defined), Z¹ is a direct bond, and A¹is —CH₂— or —CH(CH₃)—, may be prepared for example by reaction ofcompounds of formula (33):

wherein R⁴⁹ is as hereinbefore defined, R² is alkyl, aryl or heteroaryl,and R⁵⁴ is hydrogen or methyl, with palladium acetate in the presence oftriethylamine in an inert solvent such as acetonitrile, sealed in abomb, and at a temperature up to about 110° C.

Compounds of formula (33), wherein R², R⁵³ and A¹ are as hereinbeforedefined, may be prepared by reaction of compounds of formula (34):

wherein R⁵³ is as hereinbefore defined with an allyl bromide of formula(35):R²(R⁵⁴)C═CH—CHBr  (35)wherein R² and R⁵⁴ are as defined above, in the presence of lithiumdiisopropylamide in an inert solvent such as an ether, e.g.tetrahydrofuran, at a temperature from about −78° C. to about roomtemperature.

Compounds of formula (34) may be prepared according to the method ofHill, Tetrahedron, 1990, 46, page 4587.

Intermediates of formula (IV) represented by formula (36):

wherein R¹, R², A¹, and Z¹ are as hereinbefore defined, and R⁵³ isCO₂R⁴⁹, may be prepared for example by reaction of compounds of formula(37):

wherein R¹, R⁴⁹ and Z¹ are as hereinbefore defined, with compounds offormula R²A¹C≡N, wherein R² and A¹ are as hereinbefore defined (with theproviso that when A¹ is a direct bond then R² is alkyl, cycloalkyl,aryl, or heteroaryl), in the presence of an acid catalyst, such as4-toluenesulphonic acid, at a temperature up to about 180° C.

Compounds of formula (37), wherein R¹ and Z¹ are as hereinbeforedefined, may be prepared by reduction of compounds of formula (38):

wherein R¹, R⁴⁹ and Z¹ are as hereinbefore defined. The reduction may becarried out using hydrogen in the presence of a suitable metal catalyst,e.g. platinum or palladium optionally supported on an inert carrier suchas carbon, preferably in a solvent such as ethyl acetate.

Compounds of formula (38), wherein R⁴⁹ is as hereinbefore defined, R¹ ismethyl and Z¹ is an oxygen atom, may be prepared by nitration of methyl4-methoxysalicylate followed by separation of the required nitro-isomer.The nitration may be conveniently carried out using concentrated nitricacid in acetic acid at a temperature at about room temperature.

Intermediates of formula (IV) represented by formula (39):

wherein R¹ is alkyl, R² is alkyl, aryl or heteroaryl, R⁵³ is CO₂R⁴⁹ (inwhich R⁴⁹ is as hereinbefore defined), Z¹ is a direct bond, and A¹ is ashereinbefore defined, may be prepared for example by reduction ofcompounds of formula (15), wherein R¹ is alkyl, R² is alkyl, aryl orheteroaryl, R⁵³ is CO₂R⁴⁹ (in which R⁴⁹ is as hereinbefore defined), Qis CH, Z¹ is a direct bond, and A¹ is as hereinbefore defined, using asolution of borane-tetrahydrofuran complex in tetrahydrofuran. Thereaction may conveniently be carried out in trifluoroacetic acid at atemperature at about 0° C.

Intermediates of formula (IV) represented by formula (40):

wherein R¹, R², A¹ and Z¹ are as hereinbefore defined, and R⁵³ is CO₂R⁴⁹(in which R⁴⁹ is as hereinbefore defined), may be prepared for exampleby reaction of compounds of formula (37), wherein R¹, R⁴⁹ and Z¹ are ashereinbefore defined, with compounds of formula (41):R²A¹CH(Cl)C(═O)Cl  (41)wherein R¹ and A¹ are as hereinbefore defined, in an inert solvent suchas dichloromethane, in the presence of a base, such as sodium hydrogencarbonate, and at a temperature from about 0° C. to about roomtemperature, followed by heating the intermediate with potassiumcarbonate in dimethylformamide at 100° C. and then reduction withborane-dimethylsulphide complex in tetrahydrofuran at room temperature.

Intermediates of formula (IV) represented by formula (41):

wherein R¹, R⁴⁹ and Z¹ are as hereinbefore defined, R² is alkoxy,arylalkyloxy, heteroarylalkyloxy or hydroxy and A¹ is methylene may beprepared for example by reaction of compounds of formula (42):

wherein R¹, R⁴⁹ and Z¹ are as hereinbefore defined, with with sodiumhypochlorite in the presence of an aqueous acid such as dilutehydrochloric acid, in an alcohol, such as methanol, and at a temperatureat about reflux temperature, followed by treatment of the resultantchloroimine with water or an alcohol of formula R²—OH where R² is asdefined immediately above, in the presence of an alkali metal carbonate,such as potassium carbonate, at a temperature at about refluxtemperature

Compounds of formula (42) wherein R¹, R⁴⁹ and Z¹ are as hereinbeforedefined, may be prepared by reaction of compounds of formula (4) whereinR¹ and Z¹ are as hereinbefore defined, R⁵³ is CO₂R⁴⁹ (in which R⁴⁹ is ashereinbefore defined) and Q¹ is CH, with chlorocetonitrile in thepresence of an acid catalyst, such as 4-toluenesulphonic acid, and at atemperature at about 180° C.

Intermediates of formulae (II), (IV), (VI), (VIII), (X), (XIV), (XV),(XVI), (XVIII), (XX), (XXII), (XXIII), (XXV), (XXVI), (XXVII), (XXIX),(XXXI), (XXXIII), (XXXV), (XXXVII), (XXXX), (XXXXII), (XXXXIII),(XXXXV), (XXXXIX), (L), (LII), (LIV), (LV), (LVIII) and (LIX) are novelcompounds and, as such, they and their processes described herein fortheir preparation constitute further features of the present invention.

The present invention is further Exemplified but not limited by thefollowing illustrative Examples and Reference Examples.

In the nuclear magnetic resonance spectra (NMR) the chemical shifts areexpressed in ppm relative to tetramethylsilane. Abbreviations have thefollowing significances: s=singlet; d=doublet; t=triplet; m=multiplet;dd=doublet of doublets; b=broad.

EXAMPLE 1 (a)N-(3,5-Dichloro-4-pyridyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide

A solution of 4-amino-3,5-dichloropyridine (24.3 g) in tetrahydrofuran(100 ml) was diluted with toluene (150 ml) and the mixture treateddropwise with a solution of sodium diethylaluminate in toluene (36 ml; 2M, caution pyrophoric reagent). The mixture was stirred at ambienttemperature for 30 minutes, then heated at reflux with stirring for afurther 30 minutes. The resulting solution was cooled to roomtemperature and then treated with a solution of 1′-benzotriazolyl7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate [ReferenceExample 1(a)] in tetrahydrofuran (40 ml). The resulting mixture wasrefluxed for 2 hours, then cooled to ambient temperature, then dilutedwith chloroform and then washed with a dilute solution of sodiumtartrate followed by brine. The organic phase was dried over magnesiumsulphate and then evaporated. The solid residue was triturated overnightwith ethyl acetate and the insoluble material was recrystallised from amixture of methanol and toluene to give the title compound (6.06 g) as awhite solid, m.p. 230-231° C. [Elemental analysis:—C, 50.0; H, 3.60; N,14.4%. Calculated:—C, 50.4; H, 3.70; N, 14.7%].

(b) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(b), there was preparedN-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenyl-3H-benzimidazole-4-carboxamideas a white solid, m.p. 344-345° C. [Elemental analysis:—C, 57.9; H,3.40; N, 13.2%. Calculated:—C, 58.1; H, 3.41; N, 13.6%].

(c) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(c), there was preparedN-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenethyl-3H-benzimidazole-4-carboxamideas a white solid, m.p. 211° C. [Elemental analysis:—C, 60.0; H, 4.20; N,12.5%. Calculated:—C, 59.9; H, 4.11; N, 12.7%].

(d) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(d), there was prepared2-benzyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 200-201° C. [Elemental analysis:—C, 59.4; H,3.80; N, 12.8%. Calculated:—C, 59.0; H, 3.77; N, 13.1%].

(e) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(e), there was prepared(RS)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxamideas a white solid, m.p. 220-222° C. [Elemental analysis:—C, 60.3; H,4.10; N, 12.4%. Calculated:—C, 59.9; H, 4.11; N, 12.7%]. NMR (CDCl₃): δ1.90(d,J=7.5 Hz,3H), 3.97(s,3H), 4.41(q,J=7.5 Hz,1H), 6.80(d,J=8 Hz,1H),7.4(m,5H), 8.19(d,J=8 Hz,1H), 8.8(s,2H), 9.05(bs,1H).

(f) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(f), there was preparedN-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxybenzyl)-3H-benzimidazole-4-carboxamideas a white solid, m.p. 225-226° C. [Elemental analysis:—C, 57.6; H,3.90; N, 12.2%. Calculated:—C, 57.8; H, 3.97; N, 12.3%]. NMR (CDCl₃): δ3.8(s,3H), 3.95(s,3H), 4.28(s,2H), 6.79(d,J=8 Hz,1H), 6.92(d,J=8 Hz,2H),7.26(d,J=8 Hz,2H), 8.17(d,J=8 Hz,1H), 8.55(s,2H), 9.4(bs,1H).

(g) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(g), there was prepared(RS)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid; m.p. 281° C. with decomposition. [Elementalanalysis:—C, 63.5; H, 5.30; N, 10.9%. Calculated:—C, 63.7; H, 5.14; N,11.0%].

(h) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(h), there was prepared(RS)-N-(3,5-dichloro-4-pyridyl)-2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 225-226° C. [Elemental analysis:—C, 64.2; H,4.40; N, 10.5; H₂O, 2.0%. Calculated for C₂₈H₂₂Cl₂N₄O₂.0.5H₂O:—C, 63.8;H, 4.37; N, 10.6; H₂O, 1.7%].

(i) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(i), there was prepared(RS)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-phenylpropyl)-3H-benzimidazole-4-carboxamideas a white solid, m.p. 103-105° C. [Elemental analysis:—C, 60.3; H,4.50; N, 12.0%. Calculated:—C, 60.1; H, 4.43; N, 12.3%].

(j) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(j), there was preparedN-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxyphenoxymethyl)-3H-benzimidazole-4-carboxamideas a white solid, m.p. 185-186° C. [Elemental analysis:—C, 55.2; H,3.90; N, 11.4%. Calculated:—C, 55.8; H, 3.83; N, 11.8%].

(k) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(k), there was prepared(RS)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxamideas a white solid, m.p. 223-224° C. [Elemental analysis:—C, 61.0; H,4.70; N, 11.7%. Calculated:—C, 61.4; H, 4.72; N, 11.9%].

(l) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(l), there was prepared2-(4-bromobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a yellow solid, m.p. 273-275° C. [Elemental analysis:—C, 49.8; H,2.90; N, 10.6%. Calculated:—C, 49.8; H, 2.99; N, 11.1%]. NMR {(CD₃)₂SO}:δ 4.00(s,3H), 4.25(s,2H), 7.00(d,1H), 7.35(d,2H), 7.50(d,2H),7.90(d,1H), 8.74(s,1H), 12.95(s,1H), 13.40(s,1H).

(m) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(m), there was prepared(RS)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[3-methoxy-1-phenylpropyl]-3H-benzimidazole-4-carboxamideas a white solid, m.p. 167-169° C. [Elemental analysis:—C, 59.1; H,4.60; N, 11.3%. Calculated:—C, 59.3; H, 4.57; N, 11.5%]. NMR (CDCl₃): δ2.33(m,1H), 2.75(m,1H), 3.31(m,1H), 3.33(s,3H), 3.45(m,1H), 4.0(s,3H),4.50(t,J=8 Hz,1H), 6.82(d,J=8 Hz,1H), 7.35(m,5H), 8.18(d,J=8 Hz,1H),8.60(s,2H), 9.63(bs,1H).

(n) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(n), there was prepared2-(4-cyanobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 225-227° C. [Elemental analysis:—C, 58.4; H,3.60; N, 14.8%. Calculated:—C, 58.4; H, 3.34; N, 15.5%]. NMR {(CD₃)₂SO}:δ 4.05(s,3H), 4.35(s,2H), 7.00(d,1H), 7.60(d,2H), 7.75(d,2H),7.90(d,1H), 8.70(s,2H), 11.90(s,1H), 13.45(s,1H).

(o) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(o), there was preparedN-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[4-(3-pyridyl)benzyl]-3H-benzimidazole-4-carboxamideas a tan coloured solid, m.p. 255° C. with decomposition. [Elementalanalysis:—C, 61.3; H, 4.10; N, 13.2; H₂O, 0.90%. Calculated forC₂₆H₁₉Cl₂N₅O₂0.25H₂O:—C, 60.8; H, 3.70; N, 13.6, H₂O, 0.88%]. NMR{(CD₃)₂SO}: δ 4.10(s,3H), 4.35(s,2H), 7.00(d,1H), 7.50(m,3H),7.70(d,2H), 7.90(d,1H), 8.10(d,1H), 8.55(d,1H), 8.70(s,1H), 8.85(d,1H),12.00(s,1H), 13.40(s,1H).

(p) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(p), there was preparedN-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-methoxybenzyl)-3H-benzimidazole-4-carboxamideas a white solid, m.p. 211-212° C. [Elemental analysis:—C, 57.7; H,3.70; N, 12.0%. Calculated:—C, 57.8; H, 3.97; N, 12.3%].

(q) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(q), there was prepared(RS)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(methoxy-phenyl-methyl)-3H-benzimidazole-4-carboxamideas a white solid, m.p. 227-229° C. [Elemental analysis:—C, 57.8; H,3.50; N, 12.0%. Calculated:—C, 57.8; H, 3.97; N, 12.3%].

(r) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(r), there was preparedN-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-methoxyphenoxy)methyl-3H-benzimidazole-4-carboxamideas a white solid, m.p. 222-223° C. NMR (CDCl₃): δ 4.0(s,3H), 4.07(s,3H),5.5(s,2H), 6.86(d,J=8 Hz,1H), 6.97(m,2H), 7.09(m,2H), 8.2(d,J=8 Hz,1H),8.59(s,2H).

(s) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(s), there was preparedN-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(3-2pyridyl)-3H-benzimidazole-4-carboxamideas an off-white solid, m.p. 315° C. [Elemental analysis:—C, 54.4; H,3.30; N, 16.3; H₂O, 1.10%. Calculated for C₁₉H₁₃Cl₂N₅O₂.0.25H₂O:—C,54.5; H, 3.25; N, 16.7, H₂O, 1.07%].

(t) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(t), there was preparedN-(3,5-dichloro-4-pyridyl)-7-methoxy-2-isopropyl-3H-benzimidazole-4-carboxamideas a white solid, m.p. 266° C. [Elemental analysis:—C, 53.7; H, 4.40; N,14.5%. Calculated:—C, 53.8; H, 4.25; N, 14.8%].

(u) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(u), there was preparedN-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methyl-3H-benzimidazole-4-carboxamideas a white solid, m.p. 235° C. [Elemental analysis:—C, 51.3; H, 3.40; N,15.8%. Calculated:—C, 51.3; H, 3.44; N, 16.0%].

(v) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(v), there was preparedN-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenoxymethyl-3H-benzimidazole-4-carboxamideas a white solid, m.p. 215-219° C. with decomposition. [Elementalanalysis:—C, 56.4; H, 3.90; N, 12.4%. Calculated:—C, 56.9; H, 3.64; N,12.6%]. NMR [(CD₃)₂SO]: δ (Major tautomer/rotomer) 4.06(s,3H),5.40(s,2H), 6.95(m,1H), 7.1(m,3H), 7.32(m,2H), 7.98(d,J=8 Hz,1H),8.75(s,2H), 11.75(bs,1H).

(w) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(w), there was prepared2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. >250° C. [Elemental analysis:—C, 56.4; H, 4.40;N, 13.5%. Calculated:—C, 56.3; H, 4.48; N, 13.8%].

(x) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(x), there was prepared2-benzyl-N-(3,5-dichloro-4-pyridyl)-3H-benzimidazole-4-carboxamide as awhite solid, m.p. 162° C. [Elemental analysis:—C, 60.5; H, 3.80; N,13.9%. Calculated:—C, 60.5; H, 3.55; N, 14.1%].

(y) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(y), there was prepared2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-1-methyl-1H-benzimidazole-4-carboxamideas a white solid, m.p. 212° C. [Elemental analysis:—C, 57.2; H, 4.80; N,13.2%. Calculated:—C, 57.3; H, 4.81; N, 13.4%].

(z) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(z), there was prepared2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3-methyl-3H-benzimidazole-4-carboxamideas a white solid, m.p. 180° C. [Elemental analysis:—C, 57.2; H, 4.80; N,13.3%. Calculated:—C, 57.3; H, 4.81; N, 13.4%].

(aa) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(aa), there was preparedN-(3,5-dichloro-4-pyridyl)-2,7-dimethoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 238-239° C. [Elemental analysis:—C, 48.8; H,3.20; N, 15.1%. Calculated:—C, 49.1; H, 3.29; N, 15.3%].

(ab) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(ab), there was prepared2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 253-254° C. [Elemental analysis:—C, 54.13; H,3.74; N, 14.85%. Calculated:—C, 54.07; H, 3.71; N, 14.85%].

(ac) By proceeding in a similar manner to Example 1(a) but using2,6-difluoroaniline and Reference Example 1(ab), there was prepared2-cyclopropyl-N-2,6-difluorophenyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 133-135° C. [Elemental analysis:—C, 62.81; H,4.71; N, 10.42%; F, 11.55%. Calculated for C₁₈H₁₅F₂N₃O₂.0.25CH₃OH:—C,62.39; H, 4.59; N, 10.82%; F, 11.96%].

(ad) By proceeding in a similar manner to Example 1(a) but using2,6-dibromoaniline and Reference Example 1(ab), there was prepared2-cyclopropyl-N-(2,6-dibromophenyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 258-260° C. [Elemental analysis:—C, 45.71; H,3.75; N, 9.33%. Calculated for C₁₈H₁₅Br₂N₃O₂.CH₃OH:—C, 45.90; H, 3.85;N, 8.45%].

(ae) By proceeding in a similar manner to Example 1(a) but using2,6-dimethylaniline and Reference Example 1(ab), there was prepared2-cyclopropyl-N-(2,6-dimethylphenyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 247-249° C. [Elemental analysis:—C, 71.51; H,6.54; N, 12.33%. Calculated:—C, 71.62; H, 6.31; N, 12.53%].

(af) By proceeding in a similar manner to Example 1(a) but using2,4,6-trifluoraniline and Reference Example 1(ab), there was prepared2-cyclopropyl-N-(2,4,6-trifluorophenyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 161-163° C. [Elemental analysis:—C, 59.79; H,3.65; N, 11.52%; F, 11.52%. Calculated:—C, 59.83; H, 3.91; N, 11.63%; F,11.63%].

(ag) By proceeding in a similar manner to Example 1(a) but using2,6-dichloroaniline and Reference Example 1(ab), there was prepared2-cyclopropyl-N-(2,6-dichlorophenyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 225-227° C. [Elemental analysis:—C, 57.35; H,4.04; N, 11.10%; Cl, 18.78%. Calculated:—C, 57.46; H, 4.02; N, 11.17%;Cl, 18.85%].

(ah) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dimethylpyridine and Reference Example 1(ab), there wasprepared2-cyclopropyl-N-(3,5-dimethyl-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 268-270° C. [Elemental analysis:—C, 65.31; H,5.80; N, 15.88%. Calculated for C₁₉H₂₀N₄O₂.0.2CH₂Cl₂:—C, 65.26; H, 5.82;N, 15.86%].

(ai) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dimethylisoxazole and Reference Example 1(ab), there wasprepared2-cyclopropyl-N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 232-234° C. [Elemental analysis:—C, 62.32; H,5.85; N, 17.08%. Calculated:—C, 62.56; H, 5.56; N, 17.17%].

(aj) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dimethylisoxazole, there was preparedN-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamideas a white solid, m.p. 232-234° C. [Elemental analysis:—C, 58.69; H,5.50; N, 16.81%. Calculated:—C, 58.17; H, 5.49; N, 16.96%].

(ak) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dimethylpyridine and Reference Example 1(ab), there wasprepared2-cyclopropyl-N-(4-carboxy-2,6-dimethylphenyl)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 190-192° C. [Elemental analysis:—C, 62.26; H,5.74; N, 10.21%. Calculated for C₂₁H₂₁N₃O₄.1.5H₂O:—C, 62.06; H, 5.95; N,10.33%].

(al) By proceeding in a similar manner to Example 1(a) but using4-carboxy-2,6-dimethylaniline, there was preparedN-(4-carboxy-2,6-dimethylphenyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamideas a white solid, m.p. 251-253° C. [Elemental analysis:—C, 61.73; H,5.57; N, 10.59%. Calculated for C₂₀H₂₁N₃O₅.0.25H₂O:—C, 61.92; H, 5.59;N, 10.83%].

(am) By proceeding in a similar manner to Example 1(a) but using4-amino-3-chloropyridine and Reference Example 1(ax), there was preparedN-(3-chloro-4-pyridyl)-7-methoxy-2-n-propyl-3H-benzimidazole-4-carboxamideas a green solid, m.p. 272-274° C. [Elemental analysis:—C, 59.04; H,4.99; N, 15.99%. Calculated:—C, 59.22; H, 4.97; N, 16.24%].

(an) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(as), there was preparedN-(3,5-dichloro-4-pyridyl)-8-methoxy-2-n-propylquinoline-5-carboxamideas a white solid, m.p. 227-230° C. [Elemental analysis:—C, 58.43; H,4.12%. Calculated for C₁₉H₁₇Cl₂N₃O₂:—C, 58.47; H, 4.39%].

(ao) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(ac), therewas prepared1-cyclohexylmethyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-1H-indole-6-carboxamideas a white solid, m.p. 226-228° C. [Elemental analysis:—C, 61.06; H,5.23; N, 9.59%. Calculated for C₂₂H₂₃Cl₂N₃O₂:—C, 61.12; H, 5.36; N,9.72%].

(ap) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(ad), therewas prepared1-cyclohexyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-1H-indole-6-carboxamideas a white solid, m.p. 165-170° C. [Elemental analysis:—C, 60.95; H,5.85; N, 9.20%. Calculated for C₂₁H₂₁Cl₂N₃O₂:—C, 60.30; H, 5.06; N,10.04%].

(aq) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(ae), therewas prepared1-(2-cyclohexyl)ethyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-1H-indole-6-carboxamideas an off-white solid, m.p 125-140° C. [Elemental analysis:—C, 60.95; H,5.85; N, 9.20%. Calculated for C₂₃H₂₅Cl₂N₃O₂:—C, 61.87; H, 5.65; N,9.41%].

(ar) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(af), therewas prepared1-(3-cyclohexyl)propyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-1H-indole-6-carboxamideas a white solid, m.p 178° C. [Elemental analysis:—C, 62.63; H, 5.99; N,8.87%. Calculated for C₂₄H₂₇Cl₂N₃O₂:—C, 62.61; H, 5.91; N, 9.13%].

(as) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(ag), therewas prepared1-heptyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-1H-indole-6-carboxamideas a white solid, m.p 170° C. [Elemental analysis:—C, 60.72; H, 5.83; N,9.51%. Calculated for C₂₂H₂₅Cl₂N₃O₂:—C, 60.83; H, 5.80; N, 9.67%].

(at) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(ah), therewas prepared1-cycloheptylmethyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-1H-indole-6-carboxamideas a yellow solid, m.p 185° C. [Elemental analysis:—C, 61.89; H, 5.65;N, 9.41%. Calculated for C₂₃H₂₅Cl₂N₃O₂:—C, 61.6; H, 5.40; N, 9.70%].

(au) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(ai), therewas prepared1-(6,6-dimethyl-bicyclo[3.1.1.]hept-3-ylmethyl)-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-1H-indole-6-carboxamideas an off-white solid, m.p 125-140° C. [Elemental analysis:—C, 62.37; H,5.78; N, 8.51%. Calculated for C₂₃H₂₅Cl₂N₃O₂:—C, 63.50; H, 5.76; N,8.89%]. NMR (CDCl₃): δ 0.65(s,3H), 1.20(s,3H), 1.30-1.40(m,1H),1.40-1.50(m,1H), 1.65-1.70(m,1H), 1.75-1.85(m,2H), 1.90-1.95(m,1H),2.10-2.20(m,1H), 2.50-2.60(m,1H), 3.90-4.00(m,2H), 7.00(s, 1H),7.50-7.70(m,2H), 7.80(s,1H), 8.00(s,1H), 8.30(s,2H).

(av) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(aj), therewas prepared1-(3-phenyl)butyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-1H-indole-6-carboxamideas a white solid, m.p 179° C. [Elemental analysis:—C, 64.24; H, 5.12; N,8.99%. Calculated for C₂₅H₂₃Cl₂N₃O₂:—C, 64.11; H, 4.95; N, 8.97%].

(aw) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(ak), therewas preparedN-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(4-trifluoromethylbenzyl)-1H-indole-6-carboxamideas a white solid, m.p 135° C. [Elemental analysis:—C, 55.08; H, 3.37; N,8.32%. Calculated for C₂₃H₁₆Cl₂F₃N₃O₂.0.5H₂O:—C, 54.86; H, 3.41; N,8.35%]. NMR {(CD₃)₂SO}: δ 2.30(s,3H), 5.52(s,1H), 7.20-7.30(m,2H),7.52(s,1H), 7.70-7.80(m,4H), 8.12(s,1H), 8.72(s,2H), 10.30(s,1H).

(ax) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(al), therewas preparedN-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(4-methylsulphonylbenzyl)-1H-indole-6-carboxamideas a yellow solid, m.p 157-160° C. [Elemental analysis:—C, 54.72; H,4.27; N, 8.65%. Calculated for C₂₃H₁₉Cl₂N₃O₄S:—C, 54.77; H, 3.80; N,8.33%].

(ay) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(am), therewas prepared1-(1,3-benzodioxol-5-yl)methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1H-indole-6-carboxamideas a white solid, m.p. >245° C. [Elemental analysis:—C, 58.53; H, 3.77;N, 8.69%. Calculated for C₂₃H₁₇Cl₂N₃O₄:—C, 58.74; H, 3.64; N, 8.93%].

(az) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(an), therewas preparedN-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(naphthalen-2-yl)methyl-1H-indole-6-carboxamideas a white solid, m.p >230° C. NMR {(CD₃)₂SO)}: δ 2.30(s,3H);5.60(s,2H); 7.35-7.40, 7.45-7.55, 7.60-7.80 and 7.80-7.90(m,10H);8.20(s,1H); 8.70(s,2H); 10.30(s,1H).

(ba) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(ao), therewas preparedN-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)methyl-1H-indole-6-carboxamideas a beige coloured solid, m.p >150° C. with decomposition. [Elementalanalysis:—C, 57.60; H, 5.30; N, 10.00%. Calculated for C₂₁H₂₁Cl₂N₃O₃:—C,58.08; H, 4.87; N, 9.67%].

(bb) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(ap), therewas preparedN-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(tetrahydrofurfuryl)methyl-1H-indole-6-carboxamideas a yellow solid, m.p 136° C. with decomposition. [Elementalanalysis:—C, 55.08; H, 3.37; N, 8.32%. Calculated forC₂₃H₁₆Cl₂F₃N₃O₂.0.425H₂O:—C, 55.89; H, 3.26; N, 8.50%]. M⁺419.

(bc) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(aq), therewas preparedN-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(4-toluenesulphonyl)-1H-indole-6-carboxamideas a light brown solid, m.p. >127° C. with decomposition. [Elementalanalysis:—C, 53.90; H, 3.60; N, 8.40%. Calculated for C₂₂H₁₇Cl₂N₃O₄:—C,53.89; H, 3.49; N, 8.57%].

(bd) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(ar), therewas preparedN-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1-(tetrahydrofuran-3-yl)-1H-indole-6-carboxamideas a beige coloured solid, m.p. >135° C. with decomposition. [Elementalanalysis:—C, 56.00; H, 4.60; N, 9.80%. Calculated for C₁₉H₁₇Cl₂N₃O₃:—C,56.17; H, 4.22; N, 10.34%].

(be) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(at), there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide as a whitesolid, m.p. 223-225° C. [Elemental analysis:—C, 56.00; H, 3.50; N,12.90%. Calculated for C₁₅H₁₁Cl₂N₃O:—C, 56.27; H, 3.46; N, 13.12%].

(bf) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dichloro-pyridine N-oxide and Reference Example 1(au), therewas prepared1-butyloxycarbonyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-indole-6-carboxamideas a white solid. NMR {(CD₃)₂SO}: δ 1.60(s), 2.30(s), 7.60-7.70(m),7.80-7.90(s), 8.70(s), 10.50(s).

(bg) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(aw), there was preparedN-(3,5-dichloro-4-pyridyl)-1H-indole-6-carboxamide as a white solid.

(bh) By proceeding in a similar manner to Example 1(a) but usingReference Example 1(av), there was prepared1-benzyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indoline-6-carboxamideas a yellow solid, m.p. 223-225° C. [Elemental analysis:—C, 63.56; H,4.94; N, 9.53%. Calculated for C₂₂H₁₉Cl₂N₃O:—C, 64.09; H, 4.69; N,10.19%]. NMR (CD₃Cl): δ 1.20-1.30(m,1H); 1.30(m,1H); 2.90-3.00(m,1H);3.30-3.40(m,1H); 3.50-3.60(m,1H); 4.20-4.30 and 4.40-4.50(m,2H);7.00(m,1H); 7.10-7.40(m,7H); 7.70(s,1H); 8.60(s,2H).

(bi) By proceeding in a similar manner to Example 1(a) but using4-aminopyridine and Reference Example 1(ai), there was prepared1-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-3-methyl-N-(4-pyridyl)-1H-indole-6-carboxamideas a white solid. [Elemental analysis:—C, 76.08; H, 7.47; N, 10.50%.Calculated for C₂₅H₂₉N₃O.0.5H₂O:—C, 75.66; H, 7.63; N, 10.60%]. NMR(CDCl₃): δ 0.75(s,3H), 1.1(s,3H), 1.3-1.4(m,1H), 1.4-1.5(m,1H),1.6-1.8(m,4H), 1.8-1.9(m,1H), 2.05-2.15(m,1H), 2.3(s,3H),2.45-2.55(m,1H), 3.8-3.9(m,2H), 7.0(s,1H), 7.4-7.5(m,1H), 7.55-7.60,7.6-7.65(m,3H), 8.0(s,1H), 8.2(s,1H), 8.5(m,2H).

(bj) By proceeding in a similar manner to Example 1(a) but using4-hydroxyaniline and Reference Example 1(av), there was prepared1-benzyl-N-(4-hydroxyphenyl)-3-methyl-1H-indole-6-carboxamide as a whitesolid, m.p. 230-231° C. [Elemental analysis:—C, 75.46; H, 6.17; N,7.05%. Calculated for C₂₃H₂ON₂O₂.0.6H₂O:—C, 75.16; H, 5.82; N, 7.63%].NMR [(CD₃)₂CO]: δ 2.2(s,3H), 5.5(s,2H), 6.8-6.85(m,2H), 7.2-7.3(m,5H),7.55-7.6(m,3H), 7.7-7.75(m,1H), 8.1(s,1H), 8.2(s,1H), 9.4(s,1H).

(bk) By proceeding in a similar manner to Example 1(a) but using4-aminopyrimidine and Reference Example 1(ae), there was prepared1-(2-cyclohexyl)ethyl-3-methyl-N-(4-pyrimidinyl)-1H-indole-6-carboxamideas a white solid, m.p. 192-194° C. [Elemental analysis:—C, 73.22; H,7.24; N, 15.18%. Calculated for C₂₂H₂₆N₄O:—C, 72.90; H, 7.23; N,15.46%]. NMR [(CD₃)₂CO]: δ 0.9-1.1, 1.1-1.3 (m,6H), 1.6-1.9(m,7H),2.3(s,3H), 4.3-4.4(m,2H), 7.3(s,1H), 7.6-7.65, 7.8-7.85(m,2H),8.3-8.4(m,2H), 8.6-8.7(m,1H), 8.9(s,1H), 9.8(m,1H).

(bl) By proceeding in a similar manner to Example 1(a) but using4-amino-3,5-dimethyl-[1,2,4]-triazole and Reference Example 1(ai), therewas prepared1-(6,6-dimethyl-bicyclo[3.1.1hept-2-ylmethyl)-N-(3,5-dimethyl-[1,2,4-triazol-4-yl)-3-methyl-1H-indole-6-carboxamideas a white solid, m.p. 135-140° C. [Elemental analysis:—C, 69.61; H,7.64; N, 17.71%. Calculated for C₂₄H₃₁N₅O:—C, 71.13; H, 7.71; N,17.28%]. NMR (CDCl₃): δ 0.7(s,3H), 1.19(s,3H), 1.25-1.4, 1.4-1.45,1.45-1.6, 1.6-1.7, 1.7-1.8, 1.8-1.9 (m,7H), 2.0-2.1 (s,1H), 2.3(s,3H),2.35(s,3H), 2.4-2.55(m,1H), 3.-4.1(m,2H), 7.0(s,1H), 7.65-7.7,7.9-7.95(m,2H), 8.35(s,1H).

EXAMPLE 2 (a)(RS)-2-(Cyclohexyl-phenyl)methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-7-methoxy-3H-benzimidazole-4-carboxamide

A solution of(RS)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide[0.545 g, Example 1(g)] in chloroform (15 ml) was treated withmeta-chloroperbenzoic acid (1.6 g, 70%). The reaction mixture wasstirred at ambient temperature for 15 hours, then diluted withchloroform. The mixture was washed with saturated sodium bicarbonatesolution, then with water and then with brine. The organic phase wasdried over magnesium sulphate and then evaporated. The residue wassubjected to flash chromatography on silica eluting with a mixture ofethyl acetate and hexanes (2:1, v/v) to give the title compound (0.12 g)as a tan coloured solid, m.p. 310-312° C. [Elemental analysis:—C, 61.0;H, 5.00; N, 10.2; H₂O, 1.70%. Calculated for C₂₇H₂₆Cl₂N₄O₃.0.5H₂O:—C,60.6; H, 5.09; N, 10.5, H₂O, 1.07%].

(b) By proceeding in a similar manner to Example 2(a) but using Example1(i), there was prepared(RS)-N-(3,5-dichloro-1-oxido-4-pyridinio)-7-methoxy-2-(2-phenyl)propyl-3H-benzimidazole-4-carboxamideas a yellow solid, m.p. 256-258° C. [Elemental analysis:—C, 57.4; H,4.40; N, 11.4%. Calculated for C₂₃H₂₀Cl₂N₄O₃.0.5H₂O:—C, 57.1; H, 4.41;N, 11.7%].

(c) By proceeding in a similar manner to Example 2(a) but using Example1(l), there was prepared2-(4-bromobenzyl)-N-(3,5-dichloro-1-oxido-4-pyridinio)-7-methoxy-3H-benzimidazole-4-carboxamideas a pale yellow solid, m.p. 248° C. [Elemental analysis:—C, 48.1; H,3.10; N, 10.0%. Calculated for C₂₁H₁₅BrCl₂N₄O₃.0.5H₂O:—C, 57.1; H, 4.41;N, 11.7%].

(d) By proceeding in a similar manner to Example 2(a) but using Example1(n), there was prepared2-(4-cyanobenzyl)-N-(3,5-dichloro-1-oxido-4-pyridinio)-7-methoxy-3H-benzimidazole-4-carboxamideas a white solid, m.p. 253° C. with decomposition. [Elementalanalysis:—C, 53.9; H, 3.50; N, 13.8; H₂O, 4.60%. Calculated forC₂₂H₁₅Cl₂N₄O₃.1.25H₂O:—C, 53.8; H, 3.59; N, 14.3; H₂O, 4.59%].

(e) By proceeding in a similar manner to Example 2(a) but using Example1(a), there was preparedN-(3,5-dichloro-1-oxido-4-pyridinio)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamideas a white solid, m.p. 244-247° C. [Elemental analysis:—C, 48.5; H,3.60; N, 13.9%. Calculated:—C, 48.4; H, 3.55; N, 14.1%].

(f) By proceeding in a similar manner to Example 2(a) but using Example1(e), there was prepared(RS)-N-(3,5-dichloro-1-oxido-4-pyridinio)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxamideas an off-white solid. [Elemental analysis:—C, 57.1; H, 3.90; N, 12.0%.Calculated for C₂₂H₁₈Cl₂N₄O₃.0.25H₂O:—C, 57.2; H, 4.04; N, 12.1%]. NMR{(CD₃)₂SO}: δ 1.75(d,J=7.5 Hz,3H), 4.03(s,3H), 4.46(q,J=7.5 Hz,1H),6.98(d,J=8 Hz,1H), 7.3(m,5H), 7.88(d,J=8 Hz,1H), 8.77(s,2H).

EXAMPLE 3 (a)1-(2-Cyclopentyl-7-methoxy-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone

A solution of diisopropylamine (0.47 ml) in tetrahydrofuran (6 ml),cooled to −10° C., was treated dropwise, with a solution of butyllithium in hexanes (1.2 ml, 2.5 M). The resulting solution was stirredfor 10 minutes, then cooled to −78° C. and then treated dropwise with asolution of 4-picoline (0.29 ml) in tetrahydrofuran (1 ml). Thissolution was stirred for 30 minutes then treated with a solution ofmethyl 2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylate [0.274 g,Reference Example 3(t)] in tetrahydrofuran (2 ml). The cold bath wasremoved and the reaction mixture stirred for 15 minutes at ambienttemperature. The mixture was quenched with water, then diluted withethyl acetate. The organic phase was separated then washed with brine,then dried over magnesium sulphate and then evaporated. The residue wassubjected to flash chromatography on silica, eluting with a mixture ofmethanol and dichloromethane (8:92, v/v), to give the title compound(0.126 g) as a white solid. [Elemental analysis:—C, 71.7; H, 6.40; N,12.5%. Calculated:—C, 71.6; H, 6.31; N, 12.5%]. NMR (CDCl₃): δ1.63-2.05(m,6H), 2.2(m,2H), 3.33(m,1H), 4.11(s,3H), 4.35(s,2H),6.72(d,J=8 Hz,1H), 7.23(m,2H), 7.82(d,J=8 Hz,1H), 8.6(m,2H).

(b) By proceeding in a similar manner to Reference Example 3(a), butusing 3,5-dichloro-4-methylpyridine and Reference Example 3(1), therewas prepared2-(3,5-dichloro-4-pyridyl)-1-[1-(4-methoxybenzyl)-3-methyl-1H-indol-6-yl]-ethanoneas a white solid, m.p. 165-167° C. [Elemental analysis: C, 65.60; H,4.80; N, 6.20%. Calculated for C₂₄H₂₀Cl₂N₂O₂: C, 65.61; H, 4.59; N,6.38%].

(c) By proceeding in a similar manner to Reference Example 3(a), butusing 3,5-dichloro-4-methylpyridine and Reference Example 3(s), therewas prepared2-(3,5-dichloro-pyridin-4-yl)-1-[1-(1-toluene-4-sulphonyl)-3-methyl-1H-indol-6-yl]-ethanoneas a yellow solid, m.p. 193-198° C. [Elemental analysis: C, 57.90; H,3.90; N, 5.80%. Calculated for C₂₃H₁₈Cl₂N₂O₃S: C, 58.36; H, 3.83; N,5.92%].

(d) By proceeding in a similar manner to Reference Example 3(a), butusing Reference Example 3(1), there was prepared1-[1-(4-methoxybenzyl)-3-methyl-1H-indol-6-yl]-2-(4-pyridyl)-ethanone asa yellow solid, m.p. 109-110° C. [Elemental analysis: C, 77.20; H, 6.30;N, 7.40%. Calculated for C₂₄H₂₂N₂O₂.0.25H₂O: C, 76.86; H, 6.05; N,7.48%]. NMR (CDCl₃): δ 2.30(s,3H); 3.80(s,3H); 4.30(s,2H); 5.20(s,2H);6.80(s,2H); 7.00-7.05(m,3H); 7.15-7.20(m,2H); 7.55-7.60(m,1H);7.70-7.75(m,1H); 8.00(s,1H); 8.45-8.50(m,2H).

EXAMPLES 4 AND 51-(7-Methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanoneand1,3-bis-(4-pyridyl)-2-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-propan-2-ol

A solution of diisopropylamine (1.51 g) in tetrahydrofuran (15 ml),under nitrogen, cooled to −10° C. was treated with butyl lithium inhexane (6 ml, 2.5 M). The solution was cooled to −78° C. then treateddropwise with a solution of 4-picoline (1.40 g) in tetrahydrofuran (10ml) followed by a solution of methyl7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate [1,25 g,Reference Example 3(a)] in tetrahydrofuran (15 ml). The brown solutionwas allowed to warm to room temperature and the resulting yellowsuspension was filtered. The insoluble material was washed with a littletetrahydrofuran then air dried. The yellow solid (2.3 g) was dissolvedin water (75 ml) and the solution extracted three times withdichloromethane (25 ml). The combined extracts were dried over magnesiumsulphate and then evaporated. The resulting yellow solid (1.53 g) wassubjected to flash chromatography on silica eluting initially with amixture of methanol and dichloromethane (5:95, v/v) to give1-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone(0.39 g) recrystallised from toluene as a yellow solid, m.p. 218-220° C.with decomposition. [Elemental analysis:—C, 66.58; H, 5.53; N, 13.76%.Calculated:—C, 66.45; H, 5.50; N, 13.5%]; then eluting with a mixture ofmethanol and dichloromethane (1:9, v/v) to give1,3-bis-(4-pyridyl)-2-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-propan-2-ol(0.4 g) recrystallised from methanol as a white solid, m.p. 210° C. withdecomposition. [Elemental analysis:—C, 68.40; H, 5.94; N, 13.85%.Calculated:—C, 68.30; H, 5.98; N, 14.00%].

EXAMPLE 67-Methoxy-2-methoxymethyl-4-[2-(4-pyridyl)ethyl]-3H-benzimidazole

A mixture of1-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone(0.92 g, Example 4), hydrazine hydrate (0.8 ml, 98%) and potassiumhydroxide (1.6 g) in diethylene glycol (10 ml) was heated at 100° C. for5 minutes. The resulting clear solution was the heated at 160° C. for 1hour, then heated at 180° C. for 2 hours whilst removing water atintervals from an attached air condenser. The red solution was cooled toroom temperature then poured into water (200 ml). The mixture wasextracted three times with dichloromethane (100 ml). The combinedextracts were dried over magnesium sulphate and then evaporated. Theresidue was subjected to flash chromatography on silica eluting with amixture of methanol and dichloromethane (5:95, v/v). Fractionscontaining the required product were combined and evaporated. Theresulting solid was combined with material similarly prepared from 0.47g of1-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanoneand dissolved in dichloromethane (50 ml). The solution was washed withwater (100 ml) then dried over magnesium sulphate and then evaporated.The residual white solid (1.03 g) was recrystallised from toluene togive the title compound (0.95 g) as a white solid, m.p. 154-156° C.[Elemental analysis:—C, 68.09; H, 6.43; N, 13.87%. Calculated:—C, 68.67;H, 6.44; N, 14.13%].

EXAMPLE 72-(4-carboxamidobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide

A solution of2-(4-cyanobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide[0.1 g, Example 1(n)] in dimethyl sulphoxide (0.3 ml) was treated withpotassium carbonate (6 mg) and hydrogen peroxide (0.05 ml, 30%). Thereaction mixture was stirred at ambient temperature for 12 hours thentreated with water (50 ml). The resulting solid was filtered and airdried to give the title compound (77%) as a white solid, m.p. 292-293°C. [Elemental analysis:—C, 55.2; H, 3.70; N, 13.9; H₂O, 1.90%.Calculated for C₂₂H₁₇Cl₂N₅O₃.0.5H₂O:—C, 55.1; H, 3.79; N, 13.9, H₂O,1.88%]. NMR {(CD₃)₂SO}: δ 4.00(s,3H), 4.35(s,2H), 5.75(s,2H),7.00(d,1H), 7.45(d,2H), 7.80(d,2H), 7.90(d,1H), 8.70(s,2H), 11.90(s,1H),13.45(s,1H).

EXAMPLE 8[2-(3-Chlorophenoxy)-pyridin-3-yl]-(7-methoxy-2-methoxymethyl-1H-benzimidazol-4-yl)-methanone

A solution of 3-bromo-2-(3-chlorophenoxy)pyridine (0.43 g, ReferenceExample 16) in dry tetrahydrofuran (6 ml), at −70° C., was treated withbutyl lithium in hexane (0.64 ml, 2.5 M). The mixture was then stirredat −70° C. for 45 minutes then treated with a solution of1-benzotriazolyl7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate [0.177 g,Reference Example 1(a)] in dry tetrahydrofuran (2 ml) and stirring wascontinued at −70° C. for 10 minutes. The reaction mixture was allowed towarm to room temperature, then stirred at this temperature for 2 hours,then treated with aqueous ammonium chloride solution, and then extractedwith ethyl acetate (20 ml). The organic extract was dried andconcentrated to give a brown syrup which was purified by flashchromatography on silica eluting initially with a mixture of diethylether and pentane (1:1, v/v), then with a mixture of diethyl ether andpentane (7:3, v/v) and then with diethyl ether to give the titlecompound (0.04 g) as white solid, m.p. 181-183° C. [Elementalanalysis:—C, 62.17, H, 4.32, N, 10.15%. Calculated :—C, 62.35, H, 4.28,N, 9.91%]. NMR (CDCl₃):- δ 3.52(s,3H), 4.13(s,3H), 4.85(s,2H),6.73(d,J=8 Hz,1H), 7.00(m,1H), 7.12(t,J=2 Hz,1H), 7.16(m,1H), 7.2(dd,J=7Hz,J=5 Hz,1H), 7.28(t,J=8 Hz,1H), 7.55(d,J=8 Hz,1H), 7.85(dd,J=8 Hz,J=2Hz, 1H), 8.83(dd,J=4 Hz,J=1 Hz, 1H).

EXAMPLE 9 (a)N-(3,5-dichloro-1-oxido-4-pyridinio)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide

A suspension ofN-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide[17.9 g, Example 1(a)] in dichloromethane (325 ml) was treated with aperacetic acid (140 ml, 37% in acetic acid) giving a pale yellowsolution which was stirred at ambient temperature for 48 hours. Thesolution was concentrated under reduced pressure, at ambienttemperature, to remove the volatile solvent and the remaining solutionwas neutralised by the slow addition of a saturated aqueous sodiumhydrogen carbonate solution (500 ml). The solid which precipitated wascollected by filtration then washed with water and then recrystallisedfrom ethanol to give the title compound (12.7 g) as a white solid.

(b) By proceeding in a similar manner to Example 9(a) but using Example1(t), there was preparedN-(3,5-dichloro-1-oxido-4-pyridinio)-2-isopropyl-7-methoxy-3H-benzimidazole-4-carboxamiderecrystallised from ethanol as a white crystalline solid, m.p. 255-258°C. with decomposition. [Elemental analysis:—C, 51.14; H, 4.13; N,13.95%. Calculated:—C, 51.60; H, 4.05; N, 14.17%].

(c) By proceeding in a similar manner to Example 9(a) but using Example1(aa), there was preparedN-(3,5-dichloro-1-oxido-4-pyridinio)-2,7-dimethoxy-3H-benzimidazole-4-carboxamideas a cream coloured solid, m.p. decomposes above 247° C. [Elementalanalysis:—C, 45.90; H, 3.06; N, 14.28%. Calculated:—C, 46.97; H, 3.13;N, 14.62%].

EXAMPLE 102-Cyclopropyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-7-methoxy-3H-benzimidazole-4-carboxamide

2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide[0.45 g, Example 1(ab)] was treated with peracetic acid (3 ml, 32% inacetic acid) and the mixture heated at 60° C. for 2.25 hours then leftat room temperature for 18 hours. The reaction mixture was diluted withdiethyl ether (60 ml), then cooled and then filtered. The yellow solidwas heated with ethanol (40 ml) then filtered to remove a small amountof insoluble solid. The filtrate was concentrated to about 25 ml volumeand stood at ambient temperature. The resulting yellow crystals werefiltered and combined with a separate batch synthesised in a similarmanner from 0.40 g of2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide.The combined material was heated with methanol (50 ml) then filtered toremove a small amount of insoluble solid. The filtrate was concentratedto about 25 ml volume and stood at ambient temperature. The resultingyellow crystals were filtered, washed with methanol and then withdiethyl ether to give the title compound (0.185 g) as cream colouredcrystals, m.p. 271-274° C. [Elemental analysis:—C, 51.91; H, 3.59; N,14.24%. Calculated:—C, 52.12; H, 3.53; N, 14.26%].

EXAMPLE 11 (a)2-Cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazole

A stirred solution of2-cyclopropyl-7-(3,5-dimethyl-4-pyridylmethoxy)-4-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazole (3.49 mMol,Reference Example 17) in methylated spirits (50 ml) was treated withhydrochloric acid (50 ml, 5M) and the mixture was then heated at refluxfor 5 hours. The resulting solution was cooled to room temperature andthen evaporated. The residue was partitioned between water (10 ml) andethyl acetate (50 ml). The pH of the aqueous phase was adjusted to 8,with cooling, and the resulting white solid was washed with water, thenwith ethyl acetate, then dried at 70° C. to afford the title compound(0.47 g) as a cream coloured solid, m.p. 152-155° C. [Elementalanalysis:—C, 62.60; H, 6.65; N, 11.52%. Calculated:—C, 70.57; H, 6.55;N, 12.99%].

(b) By proceeding in a similar manner to Example 11(a) but usingReference Example 18, there was prepared4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-2-methoxymethyl-3H-benzimidazoleas a cream coloured solid, m.p. 196-198° C. [Elemental analysis:—C,65.74; H, 6.63; N, 12.77%. Calculated:—C, 66.04; H, 6.47; N, 12.83%].

(c) By proceeding in a similar manner to Example 11(a) but usingReference Example 36, there was prepared ethyl5-(2-cyclopropyl-7-methoxy-benzimidazole-4-yl)pyridine-2-carboxylate ascream coloured solid, m.p. 126-128° C.

(d) By proceeding in a similar manner to Example 11(a) but usingReference Example 34 there was prepared2-cyclopropyl-7-methoxy-4-(4-morpholinosulphonyl)-3H-benzimidazole aswhite solid, m.p. 294-295° C.

EXAMPLE 12 (a)1-Benzyl-7-methoxy-2-methoxymethyl-4-(2-(4-pyridyl)ethyl)-1H-benzimidazolehydrochloride dihydrate

A solution of7-methoxy-2-methoxymethyl-4-[2-(4-pyridyl)ethyl]-3H-benzimidazole (0.35g, Example 6) and dimethylformamide (10 ml) was treated with sodiumhydride (0.06 g, 60% dispersion in mineral oil) under argon. Afterstirring at room temperature the mixture was treated with benzyl bromide(0.15 ml) and stirring was continued for 16 hours. The reaction mixturewas evaporated and the residue was treated with hydrochloric acidsolution (20 ml, 1M) then washed with three portions of ethyl acetate(20 ml). The pH of the aqueous phase was adjusted to 12 by addition ofsodium hydroxide solution (1M). The resulting solid was filtered, thendried, then dissolved in isopropanol (2 ml) and then treated with a fewdrops of concentrated hydrochloric acid. The mixture was allowed tostand at room temperature for 16 hours and the solid formed wasfiltered, then washed with isopropanol and then dried at 90° C. undervacuum to give the title compound as a white solid (0.2 g), m.p.193-196° C. (decomposed). [Elemental analysis:—C, 61.3; H, 6.1; N, 9.2%.Calculated:—C, 62.6; H, 6.3; N, 9.1%].

(b) By proceeding in a similar manner to Example 12(a) but using Example1(be) and chloromethylcyclohexane there was prepared1-cyclohexylmethyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamideas a yellow solid, m.p. 147-151° C. [Elemental analysis: C, 62.97; H,5.83; N, 9.52%. Calculated for C₂₂H₂₃Cl₂N₃O.0.3H₂O: C, 62.63; H, 5.64;N, 9.97%].

(c) By proceeding in a similar manner to Example 12(a) but using Example1(be) and (2-chloroethyl)-cyclohexane, there was prepared1-(2-cyclohexyl)ethyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamideas a white solid, m.p. 163-165° C. [Elemental analysis: C, 63.00; H,5.79; N, 9.71%. Calculated for C₂₃H₂₅Cl₂N₃O.0.25H₂O: C, 63.50; H, 5.91;N, 9.97%].

(d) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 3-cyclohexyl-chloropropane there was prepared1-[3-(cyclohexyl)propyl]-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamideas a white solid, m.p. 174-176° C. [Elemental analysis: C, 64.69; H,5.98; N, 9.43%. Calculated for C₂₄H₂₇Cl₂N₃O: C, 64.89; H, 6.12; N,9.46%].

(e) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 1-chloroheptane there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-heptyl-1H-indole-6-carboxamide asa white solid, m.p. 151-152° C. [Elemental analysis: C, 62.94; H, 5.80;N, 9.84%. Calculated for C₂₂H₂₅Cl₂N₃O: C, 63.16; H, 6.02; N, 10.04%].

(i) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 2-(chloromethyl)tetrahydro-2H-pyran there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)methyl-1H-indole-6-carboxamideas a white solid, m.p. 159-161° C. [Elemental analysis: C, 60.20; H,5.30; N, 9.80%. Calculated for C₂₁H₂₁Cl₂N₃O₂: C, 60.30; H, 5.06; N,10.04%].

(j) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 2-(chloromethyl)-tetrahydrofuran there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydrofuran-2-yl)methyl-1H-indole-6-carboxamideas a yellow solid, m.p. 189-191° C. [Elemental analysis: C, 59.40; H,4.90; N, 10.00%. Calculated for C₂₀H₁₉Cl₂N₃O₂: C, 59.42; H, 4.74; N,10.39%].

(k) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 4-toluenesulphonyl chloride there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamideas a white solid, m.p. 186-190° C. [Elemental analysis: C, 55.48; H,3.95; N, 8.43%. Calculated for C₂₂H₁₇Cl₂N₃O₃S: C, 55.70; H, 3.61; N,8.86%].

(l) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 3-chlorotetrahydrofuran there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydrofuran-3-yl)-1H-indole-6-carboxamideas a beige coloured solid, m.p. 184° C. [Elemental analysis: C, 58.30;H, 4.60; N, 10.30%. Calculated for C₁₉H₁₇Cl₂N₃O₂: C, 58.48; H, 4.39; N,10.77%].

(m) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 3-methoxy-chlorocyclopentane there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3-methoxy)cyclopentyl-1H-indole-6-carboxamideas a beige coloured solid, m.p. 100-120° C. with decomposition.[Elemental analysis: C, 59.90; H, 5.10; N, 9.80%. Calculated forC₂₁H₂₁Cl₂N₃O₂: C, 60.30; H, 5.06; N, 10.04%].

(n) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 5-chloro-2-chloromethyl-thiophene there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-(5-chlorothiophen-2-yl)methyl-1H-indole-6-carboxamideas a yellow solid, m.p. >165° C. with decomposition. [Elementalanalysis: C, 52.84; H, 2.98; N, 9.04%. Calculated for C₂₀H₁₄Cl₃N₃O: C,53.29; H, 3.13; N, 9.32%].

(o) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 4-(chloromethyl)-3,5-dimethylisoxazole there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3,5-dimethylisoxazol-4-yl)methyl-1H-indole-6-carboxamideas a white solid, m.p. 243-246° C. [Elemental analysis: C, 58.62; H,4.43; N, 12.72%. Calculated for C₂₁H₁₈Cl₂N₄O₂: C, 58.75; H, 4.23; N,13.05%].

(p) By proceeding in a similar manner to Example 12(a) but usingN-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide [Example1(be)] and 4-chloromethyl-2-methyl-thiazole there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-(2-methyl-thiazol-4-yl)methyl-1H-indole-6-carboxamideas a white solid, m.p. 217-219° C. [Elemental analysis: C, 55.22; H,3.63; N, 12.74%. Calculated for C₂₀H₁₆Cl₂N₄OS.0.25H₂O: C, 55.10; H,3.82; N, 12.86%].

(q) By proceeding in a similar manner to Example 12(a) but using Example1(be) and methyl 2-chloromethylfuran-2-carboxylate there was preparedmethyl5-[6-(3,5-dichloro-pyridin-4-ylcarbamoyl)-3-methyl-indol-1-ylmethyl]-furan-2-carboxylateas a white solid, m.p. 217° C. [Elemental analysis: C, 57.03; H, 3.50;N, 8.88%. Calculated for C₂₂H₁₇Cl₂N₃O₄.0.25H₂O: C, 57.05; H, 3.81; N,9.08%].

(r) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 3-chloromethyl-5-phenyl-[1,2,4]-oxadiazole there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)methyl-1H-indole-6-carboxamideas a white solid, m.p. 225-227° C. [Elemental analysis: C, 59.24; H,3.73; N, 14.09%. Calculated for C₂₄H₁₇Cl₂N₅O₂.0.5H₂O: C, 59.13; H, 3.72;N, 14.38%].

(s) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 4-(2-chloroethyl)-morpholine there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-(2-morpholin-4-yl)ethyl-1H-indole-6-carboxamideas a yellow solid, m.p. 172° C. [Elemental analysis: C, 57.78; H, 5.07;N, 12.76%. Calculated for C₂₁H₂₂Cl₂N₄O₂: C, 58.21; H, 5.12; N, 12.93%].

(t) By proceeding in a similar manner to Example 12(a) but using Example1(be) and methyl 5-chloro-pentanoate there was prepared methyl5-[6-(3,5-dichloro-pyridin-4-ylcarbamoyl)-3-methyl-indole-1-yl]-pentanoateas a white solid, m.p. 134° C. [Elemental analysis: C, 58.09; H, 5.05;N, 9.50%. Calculated for C₂₁H₂₁Cl₂N₃O₃: C, 58.07; H, 4.87; N, 9.67%].

(u) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 4-trifluoromethylbenzyl chloride there was preparedN-(3,5-dichloro-4-pyridyl)-1-(4-trifluorobenzyl)-3-methyl-1H-indole-6-carboxamideas a white solid, m.p. 221-222° C. [Elemental analysis: C, 57.63; H,3.39; N, 8.81%. Calculated for C₂₃H₁₆Cl₂F₃N₃O: C, 57.76; H, 3.37; N,8.79%].

(v) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 4-methylsulphonylbenzyl chloride there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-(4-methylsulphonylbenzyl)-1H-indole-6-carboxamideas a white solid, m.p. 125-140° C. NMR(CDCl₃): δ 2.3(3H,s), 3.2(3H,s),5.6(2H,s), 7.3-7.4(2H,m), 7.5(1H,s), 7.6-7.75(2H,m), 7.9(2H,m),8.1(1H,s), 8.7(2H,s).

(w) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 4-methoxycarbonylbenzyl chloride there was preparedN-(3,5-dichloro-4-pyridyl)-1-(4-methoxycarbonylbenzyl)-3-methyl-1H-indole-6-carboxamideas a white solid, m.p. 172-174° C. [Elemental analysis: C, 61.10; H,4.02; N, 8.81%. Calculated for C₂₄H₁₉Cl₂N₃O₃: C, 61.55; H, 4.09; N,8.97%].

(x) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 3-nitrobenzyl chloride there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3-nitrobenzyl)-1H-indole-6-carboxamideas a yellow solid, m.p. 239-240° C. [Elemental analysis: C, 57.63; H,3.75; N, 11.80%. Calculated for C₂₂H₁₆Cl₂N₄O₃.0.25H₂O: C, 57.45; H,3.62; N, 12.19%].

(y) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 2-chloromethylnaphthalene there was preparedN-(3,5-dichloro-4-pyridyl)-1-(naphthalen-2-yl)methyl-3-methyl-1H-indole-6-carboxamideas a white solid, m.p. 241-243° C. [Elemental analysis: C, 67.32; H,4.02; N, 9.06%. Calculated for C₂₆H₁₉Cl₂N₃O.0.25H₂O: C, 67.15; H, 4.23;N, 9.05%].

(z) By proceeding in a similar manner to Example 12(a) but using Example1(be) and 2-chloromethyl-4-biphenyl there was preparedN-(3,5-dichloro-4-pyridyl)-1-(biphenyl-4-yl)methyl-3-methyl-1H-indole-6-carboxamideas a white solid, m.p. 229-230° C. [Elemental analysis: C, 68.63; H,4.63; N, 8.26%. Calculated for C₂₈H₂₁Cl₂N₃O.0.25H₂O: C, 68.48; H, 4.42;N, 8.57%].

(aa) By proceeding in a similar manner to Example 12(a) but usingExample 1(be) and 1-benzyl-2-(chloromethyl)-imidazole there was preparedN-(3,5-dichloro-4-pyridyl)-3-methyl-1-(1-benzyl-imidazol-2-yl)methyl-1H-indole-6-carboxamideas a yellow solid, m.p. 92-94° C.

EXAMPLE 13 (a)1-Cyclohexylmethyl-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-1H-indole-6-carboxamide

A solution ofN-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1H-indole-6-carboxamide(0.25 g, Example 14) in a mixture of dimethyl sulphoxide (5 ml) andtetrahydrofuran (5 ml) was added to a suspension of sodium hydride(0.045 g) in a mixture of dimethyl sulphoxide (2 ml) and tetrahydrofuran(2 ml) at 0° C. The mixture was stirred for 15 minutes then treated withcyclohexylbromide (0.142 g) in a mixture of dimethyl sulphoxide (3 ml)and tetrahydrofuran (3 ml). This mixture was stirred at 0° C. for 10minutes then allowed to warm to room temperature. The reaction mixturewas quenched with ice-water then diluted with water and then extractedthree times with dichloromethane (15 ml). The combined extracts werewashed three times with water (25 ml), then with brine (15 ml), thendried over sodium sulphate and then evaporated. The residue wassubjected to flash column chromatography on silica eluting with amixture of ethyl acetate and hexane (gradient elution, 4:1 to 4:0, v/v)to give the title compound (0.19 g) as a white solid, m.p. 127° C.

(b) By proceeding in a similar manner to Example 13(a) but using4-methoxycarbonylbenzyl bromide there was prepared1-(4-methoxycarbonylbenzyl)-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-1H-indole-6-carboxamideas a white solid, m.p 169-172° C. [Elemental analysis:—C, 57.43; H,4.26; N, 8.15%. Calculated for C₂₄H₁₉Cl₂N₃O₄.H₂O:—C, 57.36; H, 4.22; N,8.37%]. NMR {(CD₃)₂CO}: δ 2.30(s,3H); 3.80(s,3H); 5.60(s,2H);7.20-7.30(s,2H); 7.40(s,1H); 7.60-7.65(m,1H); 7.75-7.80(m,1H);7.85-7.90(m,2H); 8.29(s,1H); 8.35(s,2H); 9.50 (bs,1H).

(c) By proceeding in a similar manner to Example 13(a) but using4-carboxybenzyl bromide there was prepared1-(4-carboxybenzyl)-3-methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-1H-indole-6-carboxamideas a white solid, m.p 255-257° C. with decomposition. [Elementalanalysis:—C, 58.05; H, 3.84; N, 8.66%. Calculated for C₂₃H₁₇Cl₂N₃O₄:—C,58.74; H, 3.64; N, 8.93%].

(d) By proceeding in a similar manner to Example 13(a) but using(5-chlorothiophen-2-yl)methyl bromide there was prepared1-(5-chlorothiophen-2-yl)methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1H-indole-6-carboxamideas a beige coloured solid, m.p 140-142° C. with decomposition.[Elemental analysis:—C, 50.95; H, 3.13; N, 8.38%. Calculated forC₂₀H₁₄Cl₃N₃O₂S.0.4H₂O:—C, 50.65; H, 3.152; N, 8.87%]. NMR {(CD₃)₂SO)}: δ2.30(s,3H); 5.50(s,2H); 7.00(s,2H); 7.40-7.45(m,1H); 7.60-7.65 and7.70-7.75(m,2H); 8.20(s,1H); 8.70(s,2H); 10.30(bs,1H).

(e) By proceeding in a similar manner to Example 13(a) but using1-benzyl-2-(chloromethyl)imidazole there was prepared1-(1-benzyl-imidazol-2-yl)methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1H-indole-6-carboxamideas a white solid, m.p >112° C. with decomposition. NMR {(CD₃)₂CO)}: δ2.20(s,3H); 5.20(s,2H); 5.40(s,2H); 6.90-7.00(m,3H); 7.10-7.15(m,2H);7.15-7.20(m,3H); 7.50-7.55 and 7.70-7.75(m,1H); 8.30(s,1H); 8.40(s,2H);9.60(bs,1H).

(f) By proceeding in a similar manner to Example 13(a) but using4-(chloromethyl)-2-methylthiazole there was prepared1-(2-methylthiazol-4-yl)methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1H-indole-6-carboxamideas a yellow solid, m.p 125-127° C. with decomposition. [Elementalanalysis:—C, 53.25; H, 3.65; N, 12.25%. Calculated forC₂₀H₁₆Cl₂N₄O_(2:—C,) 53.70; H, 3.61; N, 12.52%].

(g) By proceeding in a similar manner to Example 13(a) but using methyl5-(bromomethyl)-furan-2-carboxylate there was prepared methyl5-[6-N-(3,5-dichloro-1-oxido-4-pyridinio)carbamoyl-3-methyl-indol-1-ylmethyl]-furan-2-carboxylateas a white solid, m.p 196-198° C. [Elemental analysis:—C, 57.20; H,4.80; N, 9.70%. Calculated for C₂₀H₁₉Cl₂N₃O₄:—C, 57.16; H, 4.56; N,10.00%].

(h) By proceeding in a similar manner to Example 13(a) but using4-(chloromethyl)-3,5-dimethylisoxazole there was prepared1-(3,5-dimethylisoxazol-4-yl)methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1H-indole-6-carboxamideas a yellow solid, m.p 145-148° C. [Elemental analysis:—C, 55.16; H,4.02; N, 12.10%. Calculated for C₂₁H₁₈Cl₂N₃O₃:—C, 56.64; H, 4.07; N,12.58%].

(i) By proceeding in a similar manner to Example 12(a) but using4-(chloromethyl)-2-methylthiazole there was prepared1-(2-methylthiazol-4-yl)methyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1H-indole-6-carboxamideas a yellow solid, m.p 125-127° C. with decomposition. [Elementalanalysis:—C, 53.25; H, 3.65; N, 12.25%. Calculated for C₂₀H₁₆Cl₂N₄O₂:—C,53.70; H, 3.61; N, 12.52%].

EXAMPLE 14N-(3,5-Dichloro-1-oxido-4-pyridinio)-3-methyl-1H-indole-6-carboxamide

1-Butyloxycarbonyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-indole-6-carboxamide(0.2 g, Example 1(bf) was heated at 170-180° C. for 10 minutes to givethe title compound as a white solid which was used without furtherpurification. NMR {(CD₃)₂SO}: δ 2.30(s), 7.30(s), 7.50-7.60(m), 8.00(s),8.70(s), 10.30(s), 11.20(s).

EXAMPLE 15 (a)N-(3,5-Dichloro-pyridin-4-yl)-3-ethyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide

A stirred solution ofN-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxyethyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide[0.06 g, Example 16(a)] in dichloromethane (2 ml), under nitrogen and at0° C., was treated with triethylsilane (0.028 g,) and boron trifluoridedietherate (0.015 ml). The mixture was allowed to warm to roomtemperature and then stirred at this temperature for 3 hours. Thesolution was partitioned between ethyl acetate (15 ml) and saturatedsodium bicarbonate solution (15 ml). The organic layer was dried oversodium sulphate then evaporated. The residue was subjected to flashcolumn chromatography on silica eluting with a mixture of ethyl acetateand hexane (gradient elution, 1:3 to 2:1, v/v) to give the titlecompound (22 mg) as a white solid, m.p. 147-149° C. [Elementalanalysis:—C, 56.69; H, 4.04; N, 8.15%. Calculated for C₂₃H₁₉Cl₂N₃O₃S:—C,56.56; H, 3.92; N, 8.60%].

(b) By proceeding in a similar manner to Example 15(a) but usingN-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxy-1-methyl-propyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide,Example 16(b), there was preparedN-(3,5-dichloro-pyridin-4-yl)-3-(2-methyl-propyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamideas a white solid, m.p. 104-108° C. [Elemental analysis:—C, 58.84; H,4.67; N, 7.80%. Calculated for C₂₅H₂₃Cl₂N₃O₃S:—C, 58.14; H, 4.49; N,8.14%].

EXAMPLE 16 (a)N-(3,5-Dichloro-pyridin-4-yl)-3-(1-hydroxyethyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide

A stirred solution ofN-(3,5-dichloro-pyridin-4-yl)-3-formyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide(0.1 g, Example 17) in tetrahydofuran (3 ml), at 0° C., was treated witha solution of methylmagnesium bromide in diethyl ether (0.11 ml, 3M).The mixture was allowed to warm to room temperature then stirred for 2hours. The reaction mixture was quenched with water (15 ml) and thenextracted with ethyl acetate (15 ml). The organic extract was dried oversodium sulphate then evaporated. The residue was subjected to flashcolumn chromatography on silica eluting with a mixture of ethyl acetateand hexane (2:1, v/v) to yield the title compound (68 mg) as a whitesolid, m.p. 206-211° C. [Elemental analysis:—C, 55.07; H, 4.00; N,7.92%. Calculated for C₂₃H₁₉Cl₂N₃O₄S:—C, 54.77; H, 3.80; N, 8.33%].

(b) By proceeding in a similar manner to Example 16(a) but usingisopropylmagnesium chloride there was preparedN-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxy-2-methyl-propyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide.

EXAMPLE 17N-(3,5-Dichloro-pyridin-4-yl)-3-formyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide

A stirred solution ofN-(3,5-dichloro-pyridin-4-yl)-3-formyl-1H-indole-6-carboxamide (0.518 g,Example 18) in dimethylformamide at 0° C. was treated with sodiumhydride (0.136 g). The mixture was stirred for 15 minutes, then cooledto −40° C. and then treated with 4-toluenesulphonyl chloride (0.325 g).The reaction mixture was gradually allowed to warm to −20° C. over aperiod of 90 minutes, then quenched with water (20 ml), then extractedthree times with ethyl acetate (25 ml). The combined extracts were driedover sodium sulphate then evaporated to give the title compound (800mg), which was used without further purification as a white solid, m.p.245° C. [Elemental analysis:—C, 53.91; H, 3.34; N, 8.30%. Calculated forC₂₂H₁₅Cl₂N₃O₄S:—C, 54.11; H, 3.10; N, 8.60%].

EXAMPLE 18N-(3,5-Dichloro-pyridin-4-yl)-3-formyl-1H-indole-6-carboxamide

A stirred solution of dimethylformamide (10 ml), under nitrogen and at0° C., was treated with phosphorus oxychloride (0.6 ml). After stirringfor 30 minutes at 0° C. the mixture was treated with a solution ofN-(3,5-dichloro-pyridin-4-yl)-1H-indole-6-carboxamide [1.55 g, Example1(bg)] in dimethylformamide (5 ml). The mixture was then heated at 40°C. for 45 minutes then cooled to room temperature and then partitionedbetween ethyl acetate (25 ml) and saturated sodium bicarbonate (50 ml).The organic layer was washed with water (75 ml) then dried over sodiumsulphate then evaporated. The residue was subjected to flashchromatography on silica eluting with a mixture of ethyl acetate andhexane (1:2, v/v) to yield the title compound (0.53 g) as a white solid.[Elemental analysis:—C, 53.83; H, 2.99; N, 12.31%. Calculated forC₁₅H₉Cl₂N₃O₂:—C, 53.92; H, 2.71; N, 12.57%].

EXAMPLE 191-Benzyl-4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one

A solution of sodium hydride (0.013 g) in tetrahydrofuran at 0° C.,under argon, was treated with a solution of4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one (0.184g, Example 20) and benzyl bromide (0.094 g) in dry tetrahydrofuran. Themixture was allowed to warm to room temperature then treated withN,N′-dimethylpropyleneurea (0.05 g). After stirring at room temperatureovernight the solution was partitioned between ethyl acetate (15 ml)and1N hydrochloric acid (15 ml). The organic phase was dried over magnesiumsulphate then evaporated. The residue was subjected to preparative layerchromatography on silica using a mixture of ethyl acetate and hexane(3:7, v/v) as eluent to yield the title compound (0.18 g) as an oil.[Elemental analysis:—C, 79.16; H, 6.98; N, 6.14%. Calculated forC₂₉H₃₀N₂O.H₂O:—C, 79.04; H, 7.33; N, 6.36%].

EXAMPLE 204-[3-Methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one

A solution of methyl3-(3-methyl-1-{3-(phenyl)propyl}-1H-indol-6-yl)-3-nitromethyl-propionate(0.296 g, Reference Example 38) in methanol (100 ml), under argon, wastreated with excess Raney® nickel. The argon atmosphere was replaced byhydrogen at 1 atmosphere then the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was filtered throughcelite. The filtrate was evaporated and the residual crude methyl3-(3-methyl-1-{3-(phenyl)propyl}-1H-indol-6-yl)-3-aminomethyl-propionatewas dissolved in sodium hydroxide solution (15 ml, 1N). After stirringat room temperature for 1 hour the reaction mixture was extracted threetimes with ethyl acetate (15 ml). The combined extracts were dried oversodium sulphate then evaporated. The residue was subjected topreparative layer chromatography on silica using a mixture of ethylacetate and hexane (1:1, v/v) as eluent to yield the title compound(0.198 g) as an oil. NMR (CDCl₃): δ 2.05-2.15(m); 2.30(s); 2.55-2.60(m);2.65-2.70(m); 2.85-2.95(m); 3.30-3.40(m); 3.60-3.70(m); 3.90-4.00(m);4.40-4.60(m); 6.80-7.40(m). M⁺332.1941.

EXAMPLE 211-(4-Methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-ethyl)-1H-indole

A solution of cis- andtrans-[1-(4-methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-vinyl)-1H-indole(70 mg, Example 22) in a mixture of tetrahydrofuran and methanol (20 ml;1:1, v/v) was heated at 45-50° C. under an atmosphere of hydrogen in thepresence of 6% palladium on activated charcoal then stirred overnight atroom temperature. The mixture was filtered through celite thenevaporated. The residue was subjected to high pressure liquidchromatography using a hypersilC18 BDS column (250×20 ml, 8 micron) andeluting with methanol containing 0.1% ammonium hydroxide to yield thetitle compound (13 mg) as an oil. NMR (CDCl₃): δ 2.30(s,3H);3.30-3.40(m,2H); 3.70(s,3H); 4.30-4.40(m,1H); 5.10(s,2H); 6.80-7.50(m,13H); 8.30-8.35(m,2H); 8.50(bs,2H).

EXAMPLE 22 cis- andtrans-[1-(4-Methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-vinyl)-1H-indole

A stirred solution of6-(1-hydroxy-1-phenyl-2-pyridin-4-yl)ethyl-1-(4-methoxybenzyl)-3-methyl-1H-indole(50 mg, Example 23) in benzene (1.5 ml) at 0° C. was treated with4-toluenesulphonic acid (42 mg). After stirring at 0° C. for 20 minutesthe reaction mixture was partitioned between ethyl acetate (10 ml) andsaturated sodium bicarbonate solution (10 ml). The organic layer wasdried over sodium sulphate then evaporated to yield the title compound(45 mg) as a yellow solid. [Elemental analysis:—C, 82.40; H, 6.20; N,6.30%. Calculated for C₃₀H₂₆N₂O.0.5H₂O:—C, 81.96; H, 6.20; N, 6.38%].NMR(CDCl₃): [3:1, trans:cis isomers]δ 2.30 and 2.32(s,3H); 3.78 and3.79(s,3H); 5.05 and 5.07(s,2H); 6.70-6.95, 6.95-7.05, 7.10-7.25 and7.30-7.50 (m,11H); 8.35 (bs,2H).

EXAMPLE 236-(1-hydroxy-1-phenyl-2-pyridin-4-yl)ethyl-1-(4-methoxybenzyl)-3-methyl-1H-indole

A stirred solution of 4-methylpyridine (60 mg) in tetrahydrofuran (3ml), under nitrogen and at −78° C., was treated dropwise with a solutionof n-butyllithium in hexane (0.385 ml). After 30 minutes a solution of1-(4-methoxybenzyl)-3-methyl-1H-indol-6-yl]-1-phenylmethanone (200 mg,Example 24) in tetrahydrofuran (3 ml) was added and the mixture wasstirred at −78° C. for 1 hour, then warmed to room temperature and thenstirred overnight. The reaction mixture was quenched with water (15 ml)and then extracted three times with ethyl acetate (15 ml). The combinedextracts were dried over sodium sulphate and then evaporated. Theresidue was subjected to flash column chromatography on silica elutingwith a mixture of ethyl acetate and hexane (gradient elution, 1:3 to3:1, v/v) to yield the title compound (15 mg) as a white solid.[Elemental analysis:—C, 79.5; H, 6.30; N, 6.10%. Calculated forC₃₀H₂₈N₂O₂.0.25H₂O:—C, 79.5; H, 6.34; N, 6.18%]. NMR (CDCl₃): δ2.30(3H,s), 3.5-3.7(2H,m), 3.75(3H,s), 5.05(2H,s), 6.75-7.55 (m),8.15-8.20(m,2H).

EXAMPLE 24 [1-(4-Methoxy-benzyl)-3-methyl-1H-indol-6-yl]-phenylmethanone

A stirred solution ofN-methoxy-1-(4-methoxybenzyl)-3-methyl-N-methyl-1H-indole-6-carboxamide(2.215 g, Example 25) in tetrahydrofuran (55 ml) was treated with asolution of phenylmagnesium chloride in tetrahydrofuran (9.83 ml, 2M).The solution was stirred at 0° C. for 2 hours then poured into a mixtureof ice and 1N hydrochloric acid (10 ml) and then partitioned betweenethyl acetate (50 ml) and water (50 ml). The organic layer was driedover sodium sulphate then evaporated. The residue was subjected to flashchromatography on silica eluting with a mixture of ethyl acetate andhexane (1:2, v/v) to yield the title compound (2.05 g) as a yellowsolid, m.p. 146-147° C. [Elemental analysis:—C, 80.80; H, 6.00; N,3.80%. Calculated for C₂₄H₂₁NO₂:—C, 81.10; H, 5.96; N, 3.94%].

EXAMPLE 25N-methoxy-1-(4-methoxybenzyl)-3-methyl-N-methyl-1H-indole-6-carboxamide

A stirred solution of 1-(4-methoxybenzyl)-3-methyl-1H-indole-6-carbonylchloride [2.8 g, Reference Example 42(b)] in chloroform (90 ml) at 0° C.was treated with N,O-dimethylhydroxylamine hydrochloride (0.982 g) andpyridine (1.55 ml). The solution was stirred at room temperature for 1hour then evaporated. The residue was partitioned betweendichloromethane (100 ml) and brine (50 ml). The organic layer was driedover sodium sulphate then evaporated. The residue was subjected to flashchromatography on silica eluting with a mixture of ethyl acetate andhexane (1:2, v/v) to yield the title compound (2.8 g).

EXAMPLE 26 (a)1-Benzyl-N-(3,5-dichloro-1-oxido-4-pyridinio)-3-methyl-1H-indazole-6-carboxamide

A solution of 4-amino-3,5-dichloropyridine-N-oxide (0.501 g, prepared asdescribed in the specification of International Patent ApplicationPublication No. WO 92/12961) in a mixture of toluene and tetrahydrofuran(20 ml; 1:1, v/v) was treated with trimethylaluminium (2.8 ml). Afterstirring at ambient temperature for 1 hour the mixture was treateddropwise with a solution of 1-benzyl-3-methyl-1H-indazole carbonylchloride (0.16 g, Reference Example 42(a) in dry tetrahydrofuran (25ml). Stirring was continued at ambient temperature for 2 hours then themixture was heated at 90° C. for 12 hours. The reaction mixture wascooled to room temperature then poured into water (15 ml) then extractedthree times with ethyl acetate (45 ml). The combined extracts were driedover sodium sulphate then evaporated. The residue was subjected topreparative layer chromatography on silica using a mixture of ethylacetate and hexane (2:1, v/v) as eluent to yield the title compound(0.071 g) as a white solid. [Elemental analysis:—C, 58.03; H, 3.78; N,12.60%. Calculated for C₂₁H₁₆Cl₂N₄O₂.0.5H₂O:—C, 57.79; H, 3.93; N,12.85%].

(b) By proceeding in a similar manner to Example 26(a) but using4-amino-3,5-dichloropyridine and Reference Example 42(e) there waspreparedN-(3,5-dichloro-4-pyridyl)-1-(4-methoxybenzyl)-3-methyl-1H-indazole-6-carboxamideas a white solid, m.p. 213-214° C. [Elemental analysis:—C, 59.47; H,4.21; N, 12.24%. Calculated for C₂₂H₁₈Cl₂N₄O₂.0.25H₂O:—C, 59.25; H,4.18; N, 12.57%]. NMR (CDCl₃): δ 2.60(s,3H); 3.70(s,3H); 5.50(s,2H);6.70-6.80 and 7.10-7.20(m,4H); 7.60-7.65, 7.70-7.75 and 8.00-8.05(m,3H);8.50(bs,2H).

EXAMPLE 27 (a)N-(3,5-Dichloro-1-oxido-4-pyridinio)-4-methoxy-2-methoxymethyl-benzoxazole-6-carboxamide

A stirred solution of 4-acetylamino-3,5-dichloro-pyridine N-oxide (0.64g) in dry dimethylformamide (40 ml), under nitrogen and at roomtemperature, was treated portionwise with sodium hydride (2.15 g, 60%dispersion in mineral oil). After stirring for 1.5 hours the pale yellowsolution was treated with a solution of4-methoxy-2-methoxymethyl-benzoxazole-6-carbonyl chloride [ReferenceExample 42(c), prepared from 0.68 g of4-methoxy-2-methoxymethyl-benzoxazole-6-carboxylic acid] in drydimethylformamide (15 ml) whilst maintaining the reaction temperature atabout 10° C. The reaction mixture was allowed to warm to roomtemperature, then stood at room temperature for 18 hours, then treatedwith piperidine (1 ml), then stood at room temperature for 24 hours. Themixture was evaporated and the residual dark brown oil was treated withethyl acetate, then filtered. The filtrate was treated with silica (1 g)then evaporated. The residue was subjected to flash chromatography onsilica eluting initially with dichloromethane then with a mixture ofdichloromethane and methanol (49:1,v/v) and then with a mixture ofdichloromethane and methanol (25:1,v/v). Fractions containing therequired product were combined and evaporated and the resulting whitesolid was washed with diethyl ether to give the title compound (0.44 g)as a white powder, m.p. 199-202° C. [Elemental analysis:—C, 48.26; H,3.43; N, 10.83%. Calculated:—C, 48.22; H, 3.29; N, 10.55%].

(b) By proceeding in a similar manner to Example 27(a) but using4-amino-3,5-dichloropyridine and Reference Example 42(d), there waspreparedN-(3,5-dichloro-4-pyridyl)-3-isopropyl-1-methyl-1H-indole-5-carboxamidewhich was recrystallised form toluene as a colourless solid, m.p.186-189° C.

REFERENCE EXAMPLE 1 (a) 1′-Benzotriazolyl7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate

A stirred solution of7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylic acid [10.6 g,Reference Example 2(a)] in a mixture of dichloromethane (120 ml) anddiisopropylethylamine (12.5 ml) was treated withO-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uroniumtetrafluoroborate (15.4 g). After stirring for 2 hours the reactionmixture was evaporated. The residue was treated with toluene andconcentrated under vacuum affording the title compound which was usedwithout further purification.

(b) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(b), there was prepared 1′-benzotriazolyl7-methoxy-2-phenyl-3H-benzimidazole-4-carboxylate.

(c) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(c), there was prepared 1′-benzotriazolyl7-methoxy-2-phenethyl-3H-benzimidazole-4-carboxylate.

(d) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(d), there was prepared 1′-benzotriazolyl2-benzyl-7-methoxy-3H-benzimidazole-4-carboxylate.

(e) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(e), there was prepared (RS)-1′-benzotriazolyl7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxylate.

(f) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(f), there was prepared 1′-benzotriazolyl7-methoxy-2-(4-methoxybenzyl)-3H-benzimidazole-4-carboxylate

(g) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(g), there was prepared (RS)-1′-benzotriazolyl2-(cyclohexyl-phenyl-methyl)-7-methoxy-3H-benzimidazole-4-carboxylate.

(h) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(h), there was prepared (RS)-1′-benzotriazolyl2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxylate

(i) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(i), there was prepared (RS)-1′-benzotriazolyl7-methoxy-2-(2-phenylpropyl)-3H-benzimidazole-4-carboxylate.

(j) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(j), there was prepared 1′-benzotriazolyl7-methoxy-2-(4-methoxyphenoxymethyl)-3H-benzimidazole-4-carboxylate

(k) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(k), there was prepared (RS)-1′-benzotriazolyl7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxylate.

(l) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(l), there was prepared 1′-benzotriazolyl2-(4-bromobenzyl)-7-methoxy-3H-benzimidazole-4-carboxylate.

(m) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(m), there was prepared (RS)-1′-benzotriazolyl7-methoxy-2-(3-methoxy-1-phenyl-propyl)-3H-benzimidazole-4-carboxylate.

(n) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(n), there was prepared 1′-benzotriazolyl2-(4-cyanobenzyl)-7-methoxy-3H-benzimidazole-4-carboxylate.

(o) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(o), there was prepared 1′-benzotriazolyl7-methoxy-2-(4-{3-pyridyl}benzyl)-3H-benzimidazole-4-carboxylate.

(p) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(p), there was prepared 1′-benzotriazolyl7-methoxy-2-(2-methoxybenzyl)-3H-benzimidazole-4-carboxylate.

(q) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(q), there was prepared (RS)-1′-benzotriazolyl7-methoxy-2-(methoxy-phenyl-methyl)-3H-benzimidazole-4-carboxylate.

(r) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(r), there was prepared 1′-benzotriazolyl7-methoxy-2-(2-methoxyphenoxy)methyl-3H-benzimidazole-4-carboxylate.

(s) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(s), there was prepared 1′-benzotriazolyl7-methoxy-2-(3-pyridyl)-3H-benzimidazole-4-carboxylate.

(t) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(t), there was prepared 1′-benzotriazolyl2-isopropyl-7-methoxy-3H-benzimidazole-4-carboxylate.

(u) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(u), there was prepared 1′-benzotriazolyl7-methoxy-2-methyl-3H-benzimidazole-4-carboxylate.

(v) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(v), there was prepared 1′-benzotriazolyl7-methoxy-2-phenoxymethyl-3H-benzimidazole-4-carboxylate.

(w) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(w), there was prepared 1′-benzotriazolyl2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylate.

(x) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(x), there was prepared 1′-benzotriazolyl2-benzyl-3H-benzimidazole-4-carboxylate.

(y) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(y), there was prepared 1′-benzotriazolyl2-cyclopentyl-7-methoxy-1-methyl-1H-benzimidazole-4-carboxylate.

(z) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(z), there was prepared 1′-benzotriazolyl2-cyclopentyl-7-methoxy-3-methyl-3H-benzimidazole-4-carboxylate.

(aa) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(aa), there was prepared 1′-benzotriazolyl2,7-dimethoxy-3H-benzimidazole-4-carboxylate.

(ab) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(ab), there was prepared 1′-benzotriazolyl2-cyclopropyl-7-methoxy-3H-benzimidazole-4-carboxylate.

(ac) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 28(a), there was prepared 1′-benzotriazolyl1-cyclohexylmethyl-3-methyl-1H-indole-6-carboxylate.

(ad) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 31(b), there was prepared 1′-benzotriazolyl1-cyclohexyl-3-methyl-1H-indole-6-carboxylate.

(ae) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 28(c), there was prepared 1′-benzotriazolyl1-(2-cyclohexyl)ethyl-3-methyl-1H-indole-6-carboxylate.

(af) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 28(d), there was prepared 1′-benzotriazolyl1-(3-cyclohexyl)propyl-3-methyl-1H-indole-6-carboxylate.

(ag) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 28(e), there was prepared 1′-benzotriazolyl1-heptyl-3-methyl-1H-indole-6-carboxylate.

(ah) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 31(d), there was prepared 1′-benzotriazolyl1-cycloheptylmethyl-3-methyl-1H-indole-6-carboxylate.

(ai) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 31(a), there was prepared 1′-benzotriazolyl1-(6,6-dimethyl-bicyclo[3.1.1.]hept-3-ylmethyl)-3-methyl-1H-indole-6-carboxylate.

(aj) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 28(f), there was prepared 1′-benzotriazolyl1-(3-phenyl)butyl-3-methyl-1H-indole-6-carboxylate.

(ak) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 28(g), there was prepared 1′-benzotriazolyl1-(4-trifluoromethylbenzyl)-3-methyl-1H-indole-6-carboxylate.

(al) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 28(h), there was prepared 1′-benzotriazolyl1-(4-methylsulphonylbenzyl)-3-methyl-1H-indole-6-carboxylate.

(am) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 28(i), there was prepared 1′-benzotriazolyl1-(1,3-benzodioxol-5-yl)methyl-3-methyl-1H-indole-6-carboxylate.

(an) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 28(j), there was prepared 1′-benzotriazolyl3-methyl-1-(naphthalen-2-yl)methyl-1H-indole-6-carboxylate.

(ao) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 28(k), there was prepared 1′-benzotriazolyl3-methyl-1-(tetrahydro-2H-pyran-2-yl)methyl-1H-indole-6-carboxylate.

(ap) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 28(l), there was prepared 1′-benzotriazolyl3-methyl-1-(tetrahydrofurfuryl)methyl-1H-indole-6-carboxylate.

(aq) By proceeding in a similar manner to Reference, Example 1(a) butusing Reference Example 28(m), there was prepared 1′-benzotriazolyl3-methyl-1-(4-toluenesulphonyl)-1H-indole-6-carboxylate.

(ar) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 28(n), there was prepared 1′-benzotriazolyl3-methyl-1-(tetrahydrofuran-3-yl)-1H-indole-6-carboxylate.

(as) By proceeding in a similar manner to Reference Example 1(a) butusing Reference example 26(a), there was prepared1′-benzotriazolyl-8-methoxy-2-n-propylquinoline-5-carboxylate.

(at) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 28(b), there was prepared 1′-benzotriazolyl3-methyl-1H-indole-6-carboxylate.

(au) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 32, there was prepared 1′-benzotriazolyl1-butyloxycarbonyl-3-methyl-indole-6-carboxylate.

(av) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 37, there was prepared 1′-benzotriazolyl1-benzyl-3-methyl-1H-indoline-6-carboxylate.

(aw) By proceeding in a similar manner to Reference Example 1(a) butusing 1H-indole-6-carboxylic acid, there was prepared 1′-benzotriazolyl1H-indole-6-carboxylate.

(ax) By proceeding in a similar manner to Reference Example 1(a) butusing Reference Example 2(ac), there was prepared 1′-benzotriazolyl7-methoxy-2-n-propyl-3H-benzimidazole-4-carboxylate.

REFERENCE EXAMPLE 2 a)7-Methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylic acid

A solution of methyl7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate [12.12 g,Reference Example 3(a)] in methanol (100 ml) was treated with 2M sodiumhydroxide (48 ml). The resulting mixture was heated to 50° C. thenstirred at this temperature for 6 hours. The reaction mixture wasconcentrated to half its original volume then treated with 1Mhydrochloric acid (98 ml). The solution was cooled in an icebath and theresulting solid filtered then dried under high vacuum overnight to givethe title compound (11.0 g) as a solid. M⁺236. This material was usedwithout further purification.

(b) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(b), there was prepared7-methoxy-2-phenyl-3H-benzimidazole-4-carboxylic acid as a white solid.M⁺268.

(c) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(c), there was prepared7-methoxy-2-phenethyl-3H-benzimidazole-4-carboxylic acid as a whitesolid. NMR {(CD₃)₂SO}: δ 3.10(m,2H), 3.25(m,2H), 4.05(s,3H), 6.90(d,J=8Hz,1H), 7.25(m,5H), 7.83(d,J=8 Hz,1H).

(d) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(d), there was prepared2-benzyl-7-methoxy-3H-benzimidazole-4-carboxylic acid as a solid. NMR{(CD₃)₂SO}: δ 4.00(s,3H), 4.28(s,2H), 6.92(d,J=8 Hz,1H), 7.30(m,5H),7.78(d,J=8 Hz,1H).

(e) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(e), there was prepared(RS)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxylic acid.M⁺296.

(f) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(f), there was prepared7-methoxy-2-(4-methoxybenzyl)-3H-benzimidazole-4-carboxylic acid. M⁺312.

(g) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(g), there was prepared(RS)-2-(cyclohexyl-phenyl-methyl)-7-methoxy-3H-benzimidazole-4-carboxylicacid as a tan coloured solid.

(h) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(h), there was prepared(RS)-2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxylic acid.M⁺372.

(i) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(i), there was prepared(RS)-7-methoxy-2-(2-phenylpropyl)-3H-benzimidazole-4-carboxylic acid.NMR {(CD₃)₂SO}: δ 1.20(d,3H), 3.50(m,3H), 3.95(s,3H), 7.15(m,1H),7.15-7.20(m,1H), 7.23-7.36(m,4H), 7.69(d,1H), 12.10(bs,1H).

(j) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(j), there was prepared7-methoxy-2-(4-methoxyphenoxymethyl)-3H-benzimidazole-4-carboxylic acid.M⁺328.

(k) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(k), there was prepared(RS)-7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxylic acid.M⁺324.

(l) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(l), there was prepared2-(4-bromobenzyl)-7-methoxy-3H-benzimidazole-4-carboxylic acid. NMR{(CD₃)₂SO}: δ 3.90(s,3H), 4.30(s,2H), 6.80(d,1H), 7.20(d,2H),7.40(d,2H), 7.75(d,1H).

(m) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(m), there was prepared(RS)-7-methoxy-2-(3-methoxy-1-phenyl-propyl)-3H-benzimidazole-4-carboxylicacid. M⁺340.

(n) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 14, there was prepared2-(4-cyanobenzyl)-7-methoxy-3H-benzimidazole-4-carboxylic acid. NMR{(CD₃)₂SO}: δ 4.00(s,3H), 4.35(s,2H), 6.80(d,1H), 7.35(d,2H),7.50(d,2H), 7.75(d,1H).

(o) By proceeding in a similar manner to Reference Example 2(a) butReference Example 15, there was prepared7-methoxy-2-(4-{3-pyridyl}benzyl)-3H-benzimidazole-4-carboxylic acid.NMR {(CD₃)₂SO}: δ 3.95(s,3H), 4.30(s,2H), 6.75(d,1H), 7.45(d,3H),7.70(d,3H), 8.05(dd,1H), 8.55(d,1H), 8.85(d,1H).

(p) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(n)], there was prepared7-methoxy-2-(2-methoxybenzyl)-3H-benzimidazole-4-carboxylic acid. M⁺312.

(q) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(o) or Reference Example 12, there was prepared(RS)-7-methoxy-2-(methoxy-phenyl-methyl)-3H-benzimidazole-4-carboxylicacid. M⁺312.

(r) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(p), there was prepared7-methoxy-2-(2-methoxyphenoxy)methyl-3H-benzimidazole-4-carboxylic acid.

(s) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 13, there was prepared7-methoxy-2-(3-pyridyl)-3H-benzimidazole-4-carboxylic acid.

(t) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(q), there was prepared2-isopropyl-7-methoxy-3H-benzimidazole-4-carboxylic acid as a solid. NMR{(CD₃)₂SO}: δ 1.36(d,J=6 Hz,6H), 3.50(m, 1H), 4.05(s,3H), 6.95(d,J=8Hz,1H), 7.85(d,J=8 Hz,1H).

(u) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(r), there was prepared7-methoxy-2-methyl-3H-benzimidazole-4-carboxylic acid as a white solid.M⁺206.

(v) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(s), there was prepared7-methoxy-2-phenoxymethyl-3H-benzimidazole-4-carboxylic acid as a solid.M⁺298.

(w) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(t), there was prepared2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylic acid as a solid.NMR {(CD₃)₂SO}: δ 1.68(m,2H), 1.82(m,2H), 1.94(m,2H), 2.09(m,2H),3.56(m,1H), 4.04(s,3H), 7.00(d,J=8 Hz,1H), 7.86(d,J=8 Hz,1H).

(x) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(u), there was prepared2-benzyl-3H-benzimidazole-4-carboxylic acid. M⁺252.

(y) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 5, there was prepared2-cyclopentyl-7-methoxy-1-methyl-1H-benzimidazole-4-carboxylic acid.M⁺274.

(z) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 6, there was prepared2-cyclopentyl-7-methoxy-3-methyl-3H-benzimidazole-4-carboxylic acid.

(aa) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 7, there was prepared2,7-dimethoxy-3H-benzimidazole-4-carboxylic acid. M⁺222.

(ab) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(v), there was prepared2-cyclopropyl-7-methoxy-3H-benzimidazole-4-carboxylic acid. [Elementalanalysis:—C, 62.06; H, 5.21; N, 12.05%. Calculated:—C, 62.07; H, 5.17;N, 12.07%].

(ac) By proceeding in a similar manner to Reference Example 2(a) butusing Reference Example 3(x), there was prepared7-methoxy-2-n-propyl-3H-benzimidazole-4-carboxylic acid.

REFERENCE EXAMPLE 3 (a) Methyl7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate

A solution of methyl 3-(1-imino-2-methoxy-ethylamino)-4-methoxybenzoate[15.7 g, Reference Example 4(a)] in methanol (150 ml) was treated with1M hydrochloric acid (62.6 ml) then with sodium hypochlorite solution(32.3 ml, 13%). Further aliquots of sodium hypochlorite solution wereadded until all the starting material was consumed. The solutioncontaining methyl3-(1-chloroimino-2-methoxy-ethylamino)-4-methoxybenzoate was treatedwith a saturated solution of sodium carbonate (8.62 g) in water. Themixture was then refluxed for 1 hour, then cooled to room temperature,then diluted with water and then extracted with chloroform. Thechloroform extract was washed with brine, dried over magnesium sulphateand then evaporated. The residue was subjected to flash chromatographyon silica eluting with a mixture of ethyl acetate and hexane (1:1, v/v)then with a mixture of ethyl acetate and hexane (6:1, v/v) to give thetitle compound (13.0 g) as a solid. M⁺250. NMR (CDCl₃): δ 3.48(s,3H),3.98(s,3H), 4.10(s,3H), 4.78(s,2H), 6.70(d,J=8 Hz,1H), 7.87(d,J=8Hz,1H).

(b) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(b), there was prepared methyl7-methoxy-2-phenyl-3H-benzimidazole-4-carboxylate as a solid. NMR(CDCl₃): δ 4.00(s,3H), 4.11(s,3H), 6.74(d,J=8 Hz, 1H), 7.5(m,3H),7.88(d,J=8 Hz,1H), 8.12(m,2H), 10.69(bs,1H).

(c) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(c), there was prepared methyl7-methoxy-2-phenethyl-3H-benzimidazole-4-carboxylate as a white solid.NMR (CDCl₃): δ 3.20(m, 4H), 3.90(s,3H), 4.08(s,3H), 6.70(d,J=8 Hz,1H),7.25(m,5H), 7.83(d,J=8 Hz,1H), 9.95(bs,1H).

(d) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(d), there was prepared methyl2-benzyl-7-methoxy-3H-benzimidazole-4-carboxylate. NMR (CDCl₃): δ3.90(s,3H), 4.10(s,3H), 4.35(s,2H), 6.70(d,J=8 Hz,1H), 7.30(m,5H),7.80(d,J=8 Hz,1H), 9.97(bs,1H).

(e) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(e), there was prepared (RS)-methyl7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxylate. NMR (CDCl₃):δ 1.88(d,J=7.5 Hz,3H), 3.90(s,3H), 4.10(s,3H), 4.44(q,J=7.5 Hz,1H),6.70(d,J=8 Hz,1H), 7.30(m,5H), 7.82(d,J=8 Hz,1H).

(f) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(f), there was prepared methyl7-methoxy-2-(4-methoxybenzyl)-3H-benzimidazole-4-carboxylate. NMR(CDCl₃): δ 3.80(s,3H), 3.90(s,3H), 4.08(s,3H), 4.27(s,2H), 6.69(d,J=8Hz,1H), 6.88(m,2H), 7.25(m,2H), 7.90(d,J=8 Hz,1H), 9.90(bs,1H).

(g) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(g), there was prepared (RS)-methyl2-(cyclohexyl-phenyl-methyl)-7-methoxy-3H-benzimidazole-4-carboxylate.NMR (CDCl₃): δ 0.80-1.40(m,5H), 1.6(m,5H), 2.4(m,1H), 3.86(d,1H),3.90(s,3H), 4.07(s,3H), 6.65(d,J=8 Hz,1H), 7.20(m,1H), 7.3(m,2H),7.45(m,2H), 7.78(d,J=8 Hz,1H), 10.1(bs,1H).

(h) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(h), there was prepared (RS)-methyl2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxylate as asolid.

NMR (CDCl₃): δ 3.40(dd,J=15 and 8.5 Hz,3H), 3.87(s,3H), 3.94(dd, J=15and 7 Hz,1H), 4.10(s,3H), 4.43(dd, J=8.5 and 7 Hz,1H), 6.70(d,J=8Hz,1H), 7.00-7.30 (m,10H), 7.33(d,J=8 Hz,1H), 9.93(bs,1H).

(i) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(i), there was prepared (RS)-methyl7-methoxy-2-(2-phenylpropyl)-3H-benzimidazole-4-carboxylate. NMR(CDCl₃): δ 1.38(d,3H), 3.22(d,2H), 3.36-3.49(m,1H), 3.90(s,3H),4.08(s,3H), 6.70(d,1H), 7.22-7.39(m,5H), 7.81(d,1H), 9.65(bs,1H).

(j) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example (j), there was prepared methyl7-methoxy-2-(4-methoxyphenoxymethyl)-3H-benzimidazole-4-carboxylate. NMR(CDCl₃): δ 3.79(s,3H), 3.94(s,3H), 4.10(s,3H), 5.32(s,2H), 6.71(d,J=8Hz,1H), 6.84(m,2H), 6.97(m,2H), 7.90(d,J=8 Hz,1H).

(k) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(k), there was prepared (RS)-methyl7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxylate. NMR (CDCl₃):δ 0.93(t,J=7.5 Hz,3H), 1.3(m,2H), 2.06(m,1H), 2.46(m,1H), 3.90(bs,3H),4.10(s,3H), 4.23(dd, J=9 and 7 Hz,1H), 6.69(d,J=8 Hz,1H), 7.30(m,5H),7.79(d,J=8 Hz,1H), 9.90(bs,1H).

(l) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(l), there was prepared methyl2-(4-bromobenzyl)-7-methoxy-3H-benzimidazole-4-carboxylate as a solid.NMR (CDCl₃): δ 3.90(s,3H), 4.06(s,3H), 4.25(s,2H), 6.70(d,J=8 Hz,1H),7.19(d,J=8 Hz,1H), 7.45(d,J=8 Hz,2H), 7.83(d,J=8 Hz,1H), 10.04(bs,1H).

(m) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(m), there was prepared (RS)-methyl7-methoxy-2-(3-methoxy-1-phenyl-propyl)-3H-benzimidazole-4-carboxylate.NMR (CDCl₃): δ 2.39(m,1H), 2.73(m,1H), 3.31(s,3H), 3.39(s,2H),3.91(s,3H), 4.10(s,3H), 4.50(t,J=8 Hz,1H), 6.70(d,J=8 Hz,1H),7.30(m,5H), 7.84(d,J=8 Hz,1H).

(n) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(n), there was prepared methyl7-methoxy-2-(2-methoxybenzyl)-3H-benzimidazole-4-carboxylate. NMR(CDCl₃): δ 3.92(s,3H), 4.02(s,3H), 4.03(s,3H), 4.79(s,2H), 6.62(d,J=9Hz,1H), 6.92(m,2H), 7.24(m,1H), 7.30(m,1H), 7.78(d,J=9 Hz,1H),10.58(bs,1H).

(o) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(o), there was prepared (RS)-methyl7-methoxy-2-(methoxy-phenyl-methyl)-3H-benzimidazole-4-carboxylate.

(p) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(p), there was prepared methyl7-methoxy-2-(2-methoxyphenoxy)methyl-3H-benzimidazole-4-carboxylate. NMR(CDCl₃): δ 3.95 (s,3H), 3.96(s,3H), 4.07(s,3H), 5.47(s,2H), 6.71(d,J=8Hz,1H), 6.82-7.05(m,3H), 7.10(m,1H), 7.90(d,J=8 Hz,1H).

(q) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(q), there was prepared methyl2-isopropyl-7-methoxy-3H-benzimidazole-4-carboxylate as a tan colouredsolid.

(r) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(r), there was prepared methyl7-methoxy-2-methyl-3H-benzimidazole-4-carboxylate. NMR (CDCl₃): δ2.65(s,3H), 3.96(s,3H), 4.07(s,3H), 6.68(d,J=8 Hz, 1H), 7.80(d,J=8 Hz,1H).

(s) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(s), there was prepared methyl7-methoxy-2-phenoxymethyl-3H-benzimidazole-4-carboxylate. NMR (CDCl₃): δ3.95(s,3H), 4.10(s,3H), 5.40(s,2H), 6.73(d,J=8 Hz,1H), 7.05(m,3H),7.73(m,2H), 7.90(d,J=8 Hz,1H).

(t) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(t), there was prepared methyl2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylate, as a solid. NMR(CDCl₃): δ 1.73(m,2H), 1.85(m,2H), 2.00(m,2H), 2,16(m,2H), 3.31(m,1H),3.98(s,3H), 4.08(s,3H), 6.70(d,J=8 Hz,1H), 7.80(d,J=8 Hz,1H),10.10(bs,1H).

(u) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(u), there was prepared methyl2-benzyl-3H-benzimidazole-4-carboxylate. NMR (CDCl₃): δ 3.90(s,3H),4.33(s,2H), 7.20-7.40(m,5H), 7.82(d,J=7.6 Hz,1H), 7.93(d,J=7.6 Hz,1H),10.02(bs,1H).

(v) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(v), there was prepared methyl2-cyclopropyl-7-methoxy-3H-benzimidazole-4-carboxylate, m.p. 124-126° C.[Elemental analysis:—C, 53.89; H, 5.11; N, 9.62%. Calculated:—C, 55.21;H, 5.35; N, 9.90%].

(w) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(w) and isolating the intermediate1-bromo-3-(cyclopropyl-chloroimino-methylamino)-4-methoxybenzene thentreating with potassium carbonate there was prepared4-bromo-2-cyclopropyl-7-methoxy-3H-benzimidazole as a pale brown solid,m.p. 185° C.

(x) By proceeding in a similar manner to Reference Example 3(a) butusing Reference Example 4(x), there was prepared methyl7-methoxy-2-n-propyl-3H-benzimidazole-4-carboxylate.

REFERENCE EXAMPLE 4 (a) Methyl3-(1-imino-2-methoxy-ethylamino)-4-methoxybenzoate

Method A: 4-Toluenesulphonic acid monohydrate (17.8 g) was heated undervacuum at 100° C. for 4 hours then allowed to cool to room temperatureand then treated with methoxy-acetonitrile (7.4 g) and methyl3-amino-4-methoxybenzoate (17.5 g). The resulting mixture was heated to180° C. and then stirred at this temperature for 4 hours. The reactionmixture was allowed to cool to room temperature then diluted withchloroform and then washed sequentially with 1M sodium hydroxidesolution, saturated sodium bicarbonate and brine. The organic phase wasdried over magnesium sulphate then evaporated. The residue was subjectedto flash chromatography on silica eluting initially with a mixture ofhexane and ethyl acetate (4:1, v/v) then with a mixture of hexane andethyl acetate (1:1, v/v) and finally with a mixture of ethyl acetate andtriethylamine (50:1, v/v) to give the title compound (15.79 g) as asolid. M⁺252. NMR (CDCl₃): δ 3.48(bs,3H), 3.90(bs,6H), 4.20(bs,2H),4.95(bs,1H), 6.92(d,J=8 Hz,1H), 7.60(bs,1H), 7.77(d,J=8 Hz, 1H).

Method B: A solution of methyl 2-methoxyacetimidate (36.5 g, prepared bytreating the corresponding hydrochloride [prepared according to theprocedure of C. G. Bakker et. al., Rec. Trav. Chim. Pays-Bas, 1981, 100,page 13] with aqueous sodium hydroxide) and methyl3-amino-4-methoxybenzoate (64.1 g) in butan-2-one (256 ml) was heated atreflux with stirring under a nitrogen atmosphere for 3.5 hours then afurther quantity of methyl 2-methoxyacetimidate (36.5 g) was added.After heating at reflux for a further 4 hours the reaction mixture wasleft at ambient temperature for 18 hours and then concentrated underreduced pressure. The residual brown oil was treated with cyclohexane(100 ml) and then evaporated. The residual oil was dissolved in amixture of cyclohexane and ethyl acetate (150 ml, 7:3, v/v) and heatedto 50° C. Some seed crystals of methyl3-(1-imino-2-methoxy-ethylamino)-4-methoxybenzoate were added and thenmixture was allowed to cool to ambient temperature with stirring. Theresulting solid was collected by filtration, then washed with a smallamount of a mixture of cyclohexane and ethyl acetate (7:3, v/v), andthen dried to give the title compound (62.72 g).

(b) By proceeding in a similar manner to Reference Example 4(a), methodA, but using benzonitrile, there was prepared methyl3-(imino-phenyl-methylamino)-4-methoxybenzoate as a tan coloured solid.NMR (CDCl₃): δ 3.85(s,3H), 3.86(s,3H), 6.94(bd,J=8.8 Hz,1H), 7.45(m,3H),7.65(s,1H), 7.75(m,2H), 7.90(bs,1H)]

(c) By proceeding in a similar manner to Reference Example 4(a), methodA, but using hydrocinnamonitrile, there was prepared methyl3-(1-imino-3-phenyl-propylamino)-4-methoxybenzoate as a tan colouredsolid. NMR (CDCl₃) δ 2.65(bt,2H), 3.10(bt,2H), 3.90(s,6H), 4.34(bs,1H),6.90(d,J=8 Hz,1H), 7.30(m,5H), 7.52(bs,1H), 7.74(dd,J=8 and 1 Hz,1H)]

(d) By proceeding in a similar manner to Reference Example 4(a), methodA, but using phenylacetonitrile, there was prepared methyl3-(1-imino-2-phenyl-ethylamino)-4-methoxybenzoate as a solid. M⁺298.

(e) By proceeding in a similar manner to Reference Example 4(a), methodA, but using α-methylbenzyl cyanide, there was prepared (RS)-methyl3-(1-imino-2-phenyl-propylamino)-4-methoxybenzoate. M⁺312.

(f) By proceeding in a similar manner to Reference Example 4(a), methodA, but using 4-methoxyphenylacetonitrile, there was prepared methyl3-(1-imino-2-{4-methoxyphenyl}-ethylamino)-4-methoxybenzoate. M⁺328.

(g) By proceeding in a similar manner to Reference Example 4(a), methodA, but using α-cyclohexylbenzyl cyanide, there was prepared (RS)-methyl3-(2-cyclohexyl-1-imino-2-phenyl-ethylamino)-4-methoxybenzoate as anorange solid. M⁺H 381.

(h) By proceeding in a similar manner to Reference Example 4(a), methodA, but using 2,3-diphenylpropionitrile, there was prepared (RS)-methyl3-(2,3-diphenyl-1-imino-propylamino)-4-methoxybenzoate as a solid.

(i) By proceeding in a similar manner to Reference Example 4(a), methodA, but using 3-phenylbutyronitrile, there was prepared (RS)-methyl3-(1-imino-3-phenyl-butylamino)-4-methoxybenzoate. NMR (CDCl₃): δ1.43(d,3H), 2.60(d,2H), 3.26-3.39(m,1H), 3.85(s,3H), 3.87(s,3H),4.20(bs,2H), 6.89(d,1H), 7.25-7.35(m,5H), 7.42(bs,1H), 7.75(dd,1H).

(j) By proceeding in a similar manner to Reference Example 4(a), methodA, but using 4-methoxyphenoxy-acetonitrile, there was prepared methyl3-(1-imino-2-{4-methoxyphenoxy}-ethylamino)-4-methoxybenzoate. NMR(CDCl₃): δ3.79 (s,3H), 3.88(s,3H), 3.99(s,3H), 4.74(bs,2H), 5.00(bs,1H),6.80-7.00(m,5H), 7.60(bs,1H), 7.78(dd,J=8 and 1 Hz,1H).

(k) By proceeding in a similar manner to Reference Example 4(a), methodA, but using α-propylphenylacetonitrile, there was prepared (RS)-methyl3-(1-imino-2-phenyl-pentylamino)-4-methoxybenzoate. M⁺H 341.

(l) By proceeding in a similar manner to Reference Example 4(a), methodA, but using 4-bromophenylacetonitrile, there was prepared methyl3-(2-{4-bromophenyl}-1-imino-ethylamino)-4-methoxybenzoate as a tancoloured solid. M⁺H 378. NMR (CDCl₃): δ 3.70(s,2H), 3.90(d,6H),4.35(s,1H), 6.90(d,1H), 7.30(d,2H), 7.50(m,3H), 7.75(d,1H).

(m) By proceeding in a similar manner to Reference Example 4(a), methodA, but using 4-methoxy-2-phenylbutyronitrile, there was prepared(RS)-methyl 3-(1-imino-4-methoxy-2-phenyl-butylamino)-4-methoxybenzoate.NMR (CDCl₃): δ 2.10(m,1H), 2.54(m,1H), 3.35(bs,3H), 3.40(m,1H),3.60(m,1H), 3.74(m,1H), 3.85(bs,6H), 4.25(bs,2H), 6.90(bd,J=8 Hz,1H),7.30(m,1H), 7.38(m,2H), 7.50(m,2H), 7.75(m,1H).

(n) By proceeding in a similar manner to Reference Example 4(a), methodA, but using 2-methoxyphenyl-acetonitrile, there was prepared methyl3-(1-imino-2-{2-methoxyphenyl}-ethylamino)-4-methoxybenzoate.

(o) By proceeding in a similar manner to Reference Example 4(a), methodA, but using methoxy-phenylacetonitrile, there was prepared methyl3-(1-imino-2-methoxy-2-phenyl-ethylamino)-4-methoxybenzoate.

(p) By proceeding in a similar manner to Reference Example 4(a), methodA, but using (2-methoxyphenoxy)acetonitrile, there was prepared methyl3-(1-imino-2-{2-methoxyphenoxy}-ethylamino)-4-methoxybenzoate. M⁺344.

(q) By proceeding in a similar manner to Reference Example 4(a), methodA, but using iso-butyronitrile, there was prepared methyl3-(1-imino-2-methyl-propylamino)-4-methoxybenzoate. NMR (CDCl₃): δ1.29(d,J=6 Hz,6H), 2.60(m, 1H), 3.88(bs,6H), 4.33(bs,1H), 6.89(d,J=8Hz,1H), 7.50(bs,1H), 7.72(dd,J=8 Hz,1H).

(r) By proceeding in a similar manner to Reference Example 4(a), methodA, but using acetonitrile, there was prepared methyl3-(1-imino-ethylamino)-4-methoxybenzoate. M⁺222.

(s) By proceeding in a similar manner to Reference Example 4(a), methodA, but using phenoxy-acetonitrile, there was prepared methyl3-(1-imino-2-phenoxy-ethylamino)-4-methoxybenzoate. M⁺314.

(t) By proceeding in a similar manner to Reference Example 4(a), methodA, but using cyclopentanecarbonitrile, there was prepared methyl3-(cyclopentyl-imino-methylamino)-4-methoxybenzoate as a solid. NMR(CDCl₃): δ 1.54-2.10(m,8H), 2.75(m,1H), 3.86(bs,6H), 4.30(bs,1H),6.88(bd,J=8 Hz,1H), 7.53(bs,1H), 7.73(d,J=8 Hz,1H).

(u) By proceeding in a similar manner to Reference Example 4(a), methodA, but using phenylacetonitrile and methyl 3-aminobenzoate, there wasprepared methyl 3-(2-phenyl-1-imino-ethylamino)benzoate as a tancoloured solid. M⁺312.

(v) By proceeding in a similar manner to Reference Example 4(a), methodA, but using cyclopropyl cyanide and methyl 3-amino-4-methoxybenzoate,there was prepared methyl 3-(cyclopropyl-imino-methylamino)benzoate as acolourless solid.

(w) By proceeding in a similar manner to Reference Example 4(a), methodA, but using cyclopropyl cyanide and 5-bromo-2-methoxyaniline (ReferenceExample 50), there was prepared1-bromo-3-(cyclopropyl-imino-methylamino)-4-methoxybenzene.

(x) By proceeding in a similar manner to Reference Example 4(a), methodA, but using propyl cyanide there was prepared methyl3-(propyl-imino-methylamino)-4-methoxybenzoate.

(y) By proceeding in a similar manner to Reference Example 4(a), methodA, but using 3-amino-4-methoxysalicylate (Reference Example 8(b)), therewas prepared methyl 4-methoxy-2-methoxymethyl-benzoxazole-7-carboxylateas a white solid, m.p. 104-106° C.

REFERENCE EXAMPLES 5(a) AND 6(a) Methyl2-cyclopentyl-7-methoxy-1-methyl-1H-benzimidazole-4-carboxylate andmethyl 2-cyclopentyl-7-methoxy-3-methyl-3H-benzimidazole-4-carboxylate

A suspension of sodium hydride (0.55 g, 60% dispersion in mineral oil)in dimethylformamide (1 ml), cooled to 0° C., was treated with asolution of methyl2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylate [3.61 g,Reference Example 3(t)]) in dimethylformamide (34 ml). The resultingmixture was stirred for 40 minutes then treated with iodomethane (0.82ml). The reaction mixture was allowed to stand at 4° C. for 2 days thendiluted with diethyl ether, then washed with brine, then dried overmagnesium sulphate and then evaporated. The residue was subjected toflash chromatography on silica to give methyl2-cyclopentyl-7-methoxy-1-methyl-1H-benzimidazole-4-carboxylate (3.18g), [NMR (CDCl₃): δ 1.70 (m,2H), 1.90(m,2H), 2,16(m,4H), 3.25(m,1H),3.95(s,6H), 4.00(s,3H), 6.64(d,J=8 Hz,1H), 7.89(d,J=8 Hz,1H)]; andmethyl 2-(cyclopentyl)-7-methoxy-3-methyl-3H-benzimidazole-4-carboxylate(0.37 g), [M⁺288, NMR (CDCl₃): δ 1.70(m,2H), 1.90(m,2H), 2.14(m,4H),3.25(m,1H), 3.92(s,6H), 4.02(s,3H), 6.64(d,J=8 Hz,1H), 7.75(d,J=8Hz,1H)].

(5b) By proceeding in a similar manner but using methyl3-isopropyl-1H-indole-5-carboxylate (Reference Example 52) withtetrahydrofuran as the solvent, there was prepared methyl3-isopropyl-1-methyl-1H-indole-5-carboxylate as an orange-brown colouredsolid.

REFERENCE EXAMPLE 7 Methyl 2,7-dimethoxy-3H-benzimidazole-4-carboxylate

A mixture of methyl 2,3-diamino-4-methoxybenzoate [0.5 g, ReferenceExample 8(a)] acetic acid (0.15 ml) and tetramethoxymethane (0.53 ml)was stirred at 80° C. for 40 minutes. After cooling to room temperaturethe reaction mixture was diluted with a mixture of methanol (3.6 ml), 1Nsodium hydroxide (2.55 ml) and water (8 ml). The resulting precipitatewas filtered and then passed through a short filtration silica gelcolumn to give the title compound (0.49 g) as a tan coloured solid.M⁺236. NMR (CDCl₃): δ 3.93(s,3H), 4.05(s,3H), 4.23(s,3H), 6.69(d,J=8Hz,1H), 7.74(d,J=8 Hz,1H). 9.48(bs,1H)]

REFERENCE EXAMPLE 8 (a) Methyl 2,3-diamino-4-methoxybenzoate

A solution of methyl 2-amino-4-methoxy-3-nitrobenzoate (1.84 g,Reference Example 9) in ethanol (100 ml) was treated with 10% palladiumon carbon (0.2 g). The resulting suspension was stirred under 3atmospheres of hydrogen for 3 hours. The catalyst was then removed byfiltration and the filtrate evaporated to give the title compound (1.6g) as a black solid which was used without further purification. M⁺196.

(b) By proceeding in a similar manner to Reference Example 8(a) butusing methyl 2-hydroxy-4-methoxy-3-nitrobenzoate (Reference Example 51)and ethyl acetate as the solvent, there was prepared methyl3-amino-2-hydroxy-4-methoxybenzoate as a white solid, m.p. 72-74° C.

REFERENCE EXAMPLE 9 Methyl 2-amino-4-methoxy-3-nitrobenzoate

A solution of methyl 2-carboxy-4-methoxy-3-nitrobenzoate (3.43 g,Reference Example 10) was dissolved in toluene (20 ml) was treated withthionyl chloride (1.5 ml) then with dimethylformamide (0.015 ml). Theresulting solution was stirred at reflux for 1 hour then cooled to roomtemperature and then evaporated. The residue was dissolved in acetone(20 ml) and added to a solution of sodium azide (1.3 g) in water (20 ml)cooled in an ice bath. The mixture was stirred for 1 hour then dilutedwith water. The resulting precipitate was collected by filtration. Thissolid was dissolved in a mixture of t-butanol and water (20 ml, 9:1) andgradually warmed to reflux and held at this temperature for 1 hour. Thesolution was cooled to room temperature and then evaporated. The residuewas subjected to flash chromatography on silica to give the titlecompound (1.8 g). M⁺H 227. NMR ((CD₃)₂SO): δ 3.82 (s,3H), 3.90(s,3H),6.53(d,J=8 Hz,1H), 7.1(bs,2H), 7.96(d,J=8 Hz,1H).

REFERENCE EXAMPLE 10 Methyl 2-carboxy-4-methoxy-3-nitrobenzoate

A solution of 3-nitro-4-methoxyphthallic acid (25.1 g, Reference Example11) in methanol (160 ml), cooled to 0° C., was saturated with hydrogenchloride gas then allowed to stand at 4° C. for 2 days. The reactionmixture was then diluted with water and then extracted with ether. Theether extract was washed with saturated sodium bicarbonate solution. Thebicarbonate washings were acidified and then extracted with ether. Theseether extracts were dried over magnesium sulphate and then evaporated.The residue was recrystallised from a mixture of chloroform and methanolto give the title compound (3.42 g). M⁺255. NMR {(CD₃)₂SO} δ 3.85(s,3H),4.00(s,3H), 7.55(d,J=8.5 Hz, 1H), 8.07(d,J=8.5 Hz, 1H).

A further quantity of the title compound (3.54 g) was obtained aftersubjecting the mother liquors from the recrystallisation to flashchromatography on silica.

REFERENCE EXAMPLE 11 3-Nitro-4-methoxyphthallic acid

4-Methoxyphthallic acid (21.5 g) was treated dropwise with fuming nitricacid (75 ml). The resulting mixture was heated to 60° C. and stirred for15 minutes whereupon the reaction mixture became homogenous. Thissolution was then cooled to room temperature and then diluted withwater. The mixture was extracted with diethyl ether. The combinedextracts were washed with brine then dried over magnesium sulphate andthen evaporated to give the title compound (25.1 g) as a tan colouredsolid. M⁺241.

REFERENCE EXAMPLE 12 Methyl7-methoxy-2-(α-methoxybenzyl)-3H-benzimidazole-4-carboxylate

A solution of (α-methoxy-phenylacetic acid (0.596 g) in chloroform (10ml) was treated with dimethylformamide (10 g) then with thionyl chloride(0.52 ml). The reaction mixture was stirred at ambient temperature for 2hours then evaporated. The residue was dissolved in chloroform (4 ml)and the solution added to a stirred solution of methyl2,3-diamino-4-methoxybenzoate [0.352 g, Reference Example 8(a)] in amixture of chloroform (6 ml) and triethylamine (1 ml). After stirringfor 1 hour the mixture was treated with ether and then with water. Theorganic phase was washed with sodium bicarbonate solution, then withbrine, then dried over magnesium sulphate and then evaporated. Theresidue was dissolved in acetic acid (8 ml) and the solution heated at80° C. for 1.5 hours. The solution was cooled to ambient temperaturethen diluted with ether. The mixture was washed with water, then withsodium bicarbonate solution, then with brine and then dried overmagnesium sulphate. The ethereal solution was evaporated and the residuesubjected to flash chromatography on silica eluting with a mixture ofethyl acetate and hexane (1:1, v/v) to give the tide compound (0.36 g).NMR (CDCl₃): δ 3.50(s,3H), 3.96(s,3H), 4.05(s,3H), 5.17(s,1H),6.70(d,J=8 Hz,1H), 7.24-7.40(m,3H), 7.46(m,2H), 7.85(d,J=8 Hz,1H)].

REFERENCE EXAMPLE 13 Methyl7-methoxy-2-(3-pyridyl)-3H-benzimidazole-4-carboxylate

A solution of methyl 2,3-diamino-4-methoxybenzoate [0.73 g, ReferenceExample 8(a)] and triethylamine (0.94 g) in dry dichloromethane (20 ml),at 0° C., was treated with nicotinyl chloride (0.53 g). The reactionmixture was stirred at ambient temperature for 2 hours and thenevaporated. The residue was dissolved in acetic acid (8 ml) and thesolution heated at 80° C. for 2 hours. After cooling to room temperaturethe reaction mixture was treated with water. The insoluble material wassubjected to flash chromatography on silica to give the title compound(0.46 g). NMR (CDCl₃): δ 4.00(s,3H), 4.15(s,3H), 6.70(d,1H), 7.40(m,1H),7.90(d,1H), 8.45(m,1H), 8.75(d,1H), 9.30(d,1H), 10.80(s,1H)].

REFERENCE EXAMPLE 14 Methyl2-(4-cyanobenzyl)-7-methoxy-3H-benzimidazole-4-carboxylate

A solution of methyl2-(4-bromobenzyl)-7-methoxy-3H-benzimidazole-4-carboxylate [1.4 g,Reference Example 3(1)] in dry dimethylformamide was treated withtetrakis(triphenylphosphine) palladium (0) (0.266 g) and zinc cyanide(0.275 g). The reaction mixture was heated at 100° C. for 12 hours thencooled to room temperature. The mixture was diluted with ethyl acetateand then washed with ammonium hydroxide (2N), then with water and thenwith brine. The organic solution was dried over magnesium sulphate thenevaporated. The residue was subjected to flash chromatography on silicato give the title compound (0.88 g). NMR (CDCl₃): δ 3.85(s,3H),4.00(s,3H), 4.40(s,2H), 6.70(d,1H), 7.40(d,2H), 7.65(d,2H), 7.85(d,1H).

REFERENCE EXAMPLE 15 Methyl7-methoxy-2-(4-{pyrid-3-yl}benzyl)-3H-benzimidazole-4-carboxylate

A solution of methyl2-(4-bromobenzyl)-7-methoxy-3H-benzimidazole-4-carboxylate [0.268 g,Reference Example 3(l)] in toluene (8 ml) was treated withtetrakis(triphenylphosphine) palladium (0) (0.266 g), aqueous sodiumcarbonate solution (0.5 ml, 2M) and diethyl (3-pyridyl)borane (0.085 g).The mixture was heated at reflux for 12 hours then cooled to roomtemperature. Aqueous work-up and subjected to flash chromatography onsilica to give the title compound (0.128 g). NMR {(CD₃)₂SO}: δ3.90(s,3H), 4.10(s,3H), 4.40(s,2H), 6.70(d,1H), 7.45(d,3H), 7.60(d,3H),7.90 (dd,1H), 8.60(d,1H), 8.85(d,1H), 10.10(s,1H).

REFERENCE EXAMPLE 16 3-Bromo-2-(3-chlorophenoxy)pyridine

A solution of 3-chlorophenol (5.34 g) in tetrahydrofuran (50 ml) wasadded dropwise to a suspension of sodium hydride (1.66 g, 60% dispersionin mineral oil) in tetrahydrofuran (50 ml). The solvent was evaporatedand the residue was treated with 3-bromo-2-chloropyridine (6.15 g) andthe mixture heated at 180° C. for 6 hours. The reaction mixture wascooled to 100° C., then poured into water. The mixture was extractedwith dichloromethane. The combined organic extracts were washed with 1Nsodium hydroxide, then with brine, then dried over magnesium sulphateand then evaporated. The residual brown solid was subjected to flashcolumn chromatography eluting with a mixture of ethyl acetate andpentane (2:98, v/v) to give the title compound as white solid, m.p.88-90° C. NMR (CDCl₃): δ 6.94(dd,J=7 Hz and 4 Hz,1H), 7.07(m,1H),7.19(t,J=2 Hz,1H), 7.22(m,1H), 7.35(t,J=8 Hz,1H), 7.95(dd,J=6 Hz and 1Hz,1H), 8.09(dd, J=4 Hz and 1 Hz,1H).

REFERENCE EXAMPLE 172-Cyclopropyl-7-(3,5-dimethyl-4-pyridylmethoxy)-4-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazole

A stirred solution of 2-cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazol-4-ol [0.69g, Reference Example 19(a)], triphenylphosphine (0.12 g) and(3,5-dimethyl-4-pyridyl)methanol (0.31 g, Reference Example 23) intetrahydrofuran (15 ml) was treated with diisopropyl azodicarboxylate(0.48 g). After stirring at room temperature for 4 hours the resultinghomogeneous solution was allowed to stand for a further 12 hours thenevaporated. The residue was subjected to column chromatography onneutral alumina eluting with a mixture of ethyl acetate and pentane(1:1, v/v) to give a mixture of the title compound andtriphenylphosphine oxide which was used without further purification.

REFERENCE EXAMPLE 18

By proceeding in a similar manner to Reference Example 17, but using7-methoxy-2-methoxymethyl-1(3)-(2-trimethylsilanyl-ethoxymethyl)-1H(3H)-benzimidazol-4-ol[mixture of isomers, Reference Example 19(b)], there was prepared amixture of7-(3,5-dimethyl-4-pyridylmethoxy)-4-methoxy-2-methoxymethyl-1(3)-(2-trimethylsilanyl-ethoxymethyl)-1H(3H)-benzimidazoleand triphenylphosphine oxide which was used without furtherpurification.

REFERENCE EXAMPLE 19 (a) 2-Cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazol-4-ol, isomerA

A cooled solution of 2-cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or3H)-benzimidazole-4-carbaldehyde [2.00 g, isomer A, Reference Example20(a)] in dichloromethane (40 ml) was treated with m-chloroperbenzoicacid (3.66 g). The mixture was allowed to warm to room temperature thenallowed to stand at room temperature for a further 12 hours. Thereaction mixture was diluted with dichloromethane (40 ml), then washedtwice with a saturated aqueous solution of sodium metabisulphite (100ml), then washed twice with a saturated aqueous solution of sodiumhydrogen carbonate (100 ml), then washed with brine (100 ml), then driedover magnesium sulphate and then evaporated to yield the title compoundas a colourless oil.

(b) By proceeding in a similar manner to Reference Example 19(a), butusing Reference Example 20(b), there was prepared7-methoxy-2-methoxymethyl-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazol-4-ol.

REFERENCE EXAMPLE 20 (a) 2-Cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or3H)-benzimidazole-4-carbaldehyde, isomer A

A stirred solution of2-cyclopropyl-7-methoxy-3H-benzimidazole-4-carbaldehyde [7.23 g,Reference Example 21(a)] in dry dimethylformamide (115 ml), at roomtemperature and under nitrogen, was treated portionwise with sodiumhydride (1.60 g, 60% dispersion in mineral oil,). After stirring for afurther 40 minutes the orange-brown suspension was treated dropwise with2-(trimethylsilyl)ethoxymethyl chloride (7.15 ml), over 30 minutes. Theresulting yellow-orange suspension was allowed to stand at roomtemperature for 12 hours then treated carefully with a little water. Themixture was evaporated to yield a yellow oil which was dissolved inethyl acetate (400 ml). The solution was washed twice with water (100ml), then dried over magnesium sulphate and then evaporated to yield ayellow oil (10.5 g) which was subjected to flash chromatography onsilica, eluting with a mixture of dichloromethane and methanol (99:1,v/v) to give2-cyclopropyl-7-methoxy-1(3)-(2-trimethylsilanyl-ethoxymethyl)-1H(3H)-benzimidazole-4-carbaldehyde(mixture of isomers), as a yellow oil (7.00 g). The mixture of isomerswas further subjected to flash chromatography on silica, eluting with amixture of dichloromethane and methanol (99:1, v/v) to give2-cyclopropyl-7-methoxy-1(or 3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or3H)-benzimidazole-4-carbaldehyde (isomer A).

(b) By proceeding in a similar manner to Reference Example 20(a), butusing Reference Example 21(b), there was prepared7-methoxy-2-methoxymethyl-1(3)-(2-trimethylsilanyl-ethoxymethyl)-1H(3H)-benzimidazole-4-carbaldehyde,(mixture of isomers), as a pale yellow oil.

(c) By proceeding in a similar manner to Reference Example 20(a), butReference Example 3(w) there was prepared4-bromo-2-cyclopropyl-7-methoxy-1(3)-(2-trimethylsilanyl-ethoxymethyl)-1H(3H)-benzimidazole,(mixture of isomers), as a yellow oil. The mixture of isomers wassubjected to flash chromatography on silica, eluting with a mixture ofdichloromethane and methanol (99:1, v/v) to give4-bromo-2-cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazole, (isomerA).

REFERENCE EXAMPLE 21 (a)2-Cyclopropyl-7-methoxy-3H-benzimidazole-4-carbaldehyde

A stirred suspension of2-cyclopropyl-7-methoxy-3H-benzimidazole-4-methanol [7.73 g, ReferenceExample 22(a)] in a mixture of toluene (250 ml) and dichloromethane (150ml), at room temperature and under nitrogen, was treated portionwisewith activated manganese dioxide (11 g). The resulting suspension wasstirred under nitrogen at 85° C. for 3 hours. The suspension was allowedto cool slightly and was then filtered through hyflosupercel washing thefilter pad six times with hot ethyl acetate (50 ml). The combinedfiltrate and washings were dried over magnesium sulphate and thenevaporated to yield the title compound as a cream coloured powder (7.26g).

(b) By proceeding in a similar manner to Reference Example 22(a), butusing Reference Example 22(b), there was prepared7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carbaldehyde as a paleyellow solid.

REFERENCE EXAMPLE 22 (a)2-Cyclopropyl-7-methoxy-3H-benzimidazole-4-methanol

A stirred solution of methyl2-cyclopropyl-7-methoxy-3H-benzimidazole-4-carboxylate [15.5 g,Reference Example 3(v)], in dry tetrahydrofuran (220 ml), at −78° C. andunder nitrogen, was treated dropwise over 3 hours with a solution ofdiisobutylaluminium hydride in dichloromethane (270 ml, 1.0M). Thereaction mixture was allowed to warm to room temperature over 30minutes, then cooled to −78° C., then treated dropwise with water (27ml), then allowed to warm to room temperature. The reaction mixture wasdiluted with ice-water (500 ml) and the pH of the mixture was adjustedto above 12 by the addition of aqueous sodium hydroxide (750 ml, 1M).The resulting white suspension was filtered to yield a clear filtratewhich was extracted seven times with ethyl acetate (500 ml). Thecombined extracts were dried over magnesium sulphate and then evaporatedto yield the title compound as a cream coloured powder (10.13 g).

b) By proceeding in a similar manner to Reference Example 22(a), butusing Reference Example 3(a), there was prepared7-methoxy-2-methoxymethyl-3H-benzimidazole-4-methanol as a creamcoloured solid.

c) By proceeding in a similar manner to Reference Example 22(a), butusing Reference Example 41 there was prepared3-methyl-1-{3-(phenyl)propyl}-1H-indole-6-methanol.

REFERENCE EXAMPLE 23 (3,5-Dimethyl-4-pyridyl)methanol

A stirred solution of 3,5-dimethyl-pyridyl-4-carbaldehyde (2.3 g,Reference Example 24) in methylated spirit (50 ml), at room temperatureand under nitrogen, was treated with powdered sodium borohydride (1.28g). After stirring for 6 hours the resulting homogeneous solution wasallowed to stand at room temperature for a further 12 hours then treatedwith water (10 ml). The reaction mixture was evaporated, then azeotropedwith toluene. The residue was extracted three times with hotdichloromethane (100 ml). The combined extracts were evaporated toafford a white solid which was subjected to flash chromatography onsilica, eluting with a mixture of ethyl acetate and pentane (1:1, v/v)to afford the title compound (1.2 g) as a white solid, m.p. 93-95° C.

REFERENCE EXAMPLE 24 3,5-Dimethyl-pyridine-4-carbaldehyde

A stirred solution of 4-bromo-3,5-dimethylpyridine (3.72 g, ReferenceExample 25) in diethyl ether (50 ml), at −78° C. and under nitrogen, wastreated dropwise with n-butyl lithium (0.025 ml, 1.6M). After stirringat −78° C. for 1 hour the resulting homogeneous solution was treatedwith dry dimethylformamide (6 ml) whilst maintaining the temperaturebelow −65° C. The reaction mixture was allowed to warm to roomtemperature over 1 hour, then treated with a saturated aqueous solutionof ammonium chloride (10 ml), and then extracted twice with ethylacetate (100 ml). The combined extracts were evaporated to yield anorange oil which was subjected to flash chromatography on silica,eluting with a mixture of ethyl acetate and pentane (1:4, v/v) to affordthe title compound (2.3 g) as a semi-solid.

REFERENCE EXAMPLE 25 4-Bromo-3,5-dimethylpyridine

By proceeding in a similar manner to the procedure contained in J. Chem.Soc., 1956, page 771 but using 4-nitro-3,5-dimethylpyridine-N-oxide(23.06 g), phosphorous tribromide (111.47 g) in toluene (50 ml) therewas prepared the title compound (8 g) as a yellow oil.

REFERENCE EXAMPLE 26 (a) 8-Methoxy-2-n-propylquinoline-5-carboxylic acid

A mixture of methyl 8-methoxy-2-n-propylquinoline-5-carboxylate (1.0 g,Reference Example 27), potassium carbonate (0.8 g), methanol (30 ml),and water (2 ml) was refluxed for 5 hours. The solution wasconcentrated, then diluted with water and then washed with diethylether. The pH of the aqueous phase was adjusted to 6 by addition ofhydrochloric acid (6M). The resulting cream precipitate was washed withwater and then dried at 60° C. to give the title compound (0.43 g) as acream coloured solid, m.p. 214-217° C. [Elemental analysis:—C,67.00;H,6.32; N,5.53%. Calculated for C₁₄H₁₅NO₃.0.25H₂O:—C,67.30; H,6.06;N,5.61%].

b) By proceeding in a similar manner to Reference Example 26(a), butusing Reference Example 4(y), there was prepared4-methoxy-2-methoxymethyl-benzoxazole-7-carboxylic acid as a creamcoloured solid.

c) By proceeding in a similar manner to Reference Example 26(a), butusing Reference Example 5(b), there was prepared3-isopropyl-1-methyl-1H-indole-5-carboxylic acid as a cream colouredsolid.

REFERENCE EXAMPLE 27 Methyl-8-methoxy-2-n-propylquinoline-5-carboxylate

Methyl-3-amino-4-methoxybenzoate (100 g) was treated with concentratedhydrochloric acid (14 ml) and n-butanol (10 ml), under nitrogen, withstirring. The stirred mixture was treated with p-chloranil (13.65 g) andthen heated at reflux whilst a mixture of trans-2-hexanal (8 ml) andn-butanol (5 ml) was added dropwise over 2 hours using a syringe pump.After heating at reflux for a further 30 minutes the mixture was treatedwith a solution of anhydrous zinc chloride (7.52 g) in tetrahydrofuran(60 ml), then allowed to cool slowly to room temperature and then cooledto 0° C. for 18 hours. The reaction mixture was evaporated, then dilutedwith hydrochloric acid (1M) and then washed with diethyl ether. The pHof the solution was adjusted to 6 and the resulting emulsion was treatedwith ammonium hydroxide and the solution extracted with diethyl ether.The combined dark green extracts were dried over magnesium sulphate thenevaporated. The resulting dark green oil was subjected to flashchromatography on silica eluting with a mixture of ethyl acetate andpentane (3:7, v/v) to give the title compound (1.5 g) as an orange oil.NMR(CDCl₃): δ 9.36(d,J=8.9 Hz, 1H), 8.26(d,J=8.4 Hz, 1H), 7.47(d,J=8.9Hz, 1H), 7.03(d,J=8.4 Hz, 1H), 4.14(s,3H), 3.97(s,3H), 3.02(m,2H),1.86(m,2H), 1.03(t,J=7.3 Hz,3H).

REFERENCE EXAMPLE 28 (a)1-Cyclohexylmethyl-3-methyl-1H-indole-6-carboxylic acid

A mixture of methyl 1-cyclohexylmethyl-3-methyl-1H-indole-6-carboxylate[9.0 g, Reference Example 29(a)] and lithium hydroxide (8.0 g) inaqueous methanol (300 ml, 1:2, v/v) was heated at 70° C. for 4 hours.The reaction mixture was cooled to room temperature, then acidified byaddition of dilute hydrochloric acid and then extracted three times withethyl acetate (150 ml). The combined extracts were dried over sodiumsulphate then evaporated to give the title compound as a white solid(7.3 g). M⁺271.

(b) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 30, there was prepared3-methyl-1H-indole-6-carboxylic acid as a white solid. NMR (CD₃OD): δ2.10(s), 7.10(s), 7.30-7.40(m), 7.50-7.60(m), 8.00(s).

(c) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 29(b), there was prepared1-(2-cyclohexyl)ethyl-3-methyl-1H-indole-6-carboxylic acid as a whitesolid.

(d) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 29(c), there was prepared1-(3-cyclohexyl)propyl-3-methyl-1H-indole-6-carboxylic acid as a whitesolid. NMR (CDCl₃): δ 0.80-0.90, 1.00-1.30, 1.60-1.70 and1.79-1.80(m,15H); 2.30(s,3H); 4.00-4.10(m,2H); 7.00(s, 1H);7.50-7.60(m,1H); 7.80-7.90(m, 1H); 8.20(s, 1H).

(e) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 29(d), there was prepared1-heptyl-3-methyl-1H-indole-6-carboxylic acid.

(f) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 29(e), there was prepared1-(3-phenyl)butyl-3-methyl-1H-indole-6-carboxylic acid as a white solid.NMR (CDCl₃): δ 1.60-1.70(m,2H); 1.80-1,90(m,2H); 2.30(s,3H);2.60-2.70(m,2H); 4.10-4.20(m,2H); 7.00(s, 1H); 7.10-7.30(m,5H);7.50-7.60(m, 1H); 7.80-7.90(m, 1H); 8.20(s, 1H).

(g) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 29(f), there was prepared1-(4-trifluoromethylbenzyl)-3-methyl-1H-indole-6-carboxylic acid as awhite solid. NMR {(CD₃)₂SO}: δ 2.30(s), 5.50(s), 7.20-7.30(m),7.30-7.40(m), 7.60-7.70(m), 7.90(s).

(h) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 29(g), there was prepared1-(4-methylsulphonylbenzyl)-3-methyl-1H-indole-6-carboxylic acid as awhite solid.

(i) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 29(h), there was prepared1-(1.3-benzodioxol-5-yl)methyl-3-methyl-1H-indole-6-carboxylic acid.

(j) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 29(i), there was prepared1-(naphthalen-2-yl)methyl-3-methyl-1H-indole-6-carboxylic acid as awhite solid. NMR {(CD₃)₂SO}: δ 2.30(s), 5.60(s), 7.30-8.10(m).

(k) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 29(j), there was prepared1-(tetrahydro-2H-pyran-2-yl)methyl-3-methyl-1H-indole-6-carboxylic acid.

(l) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 29(k), there was prepared3-methyl-1-(tetrahydrofurfuryl)-1H-indole-6-carboxylic acid, as a whitesolid, m.p. 217-219° C. [Elemental analysis: C,69.3; H,6.6; N,5.2%.Calculated for C₁₅H₇NO₃: C,69.48; H,6.61; N,5.40%].

(m) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 29(l), there was prepared3-methyl-1-(4-toluenesulphonyl)-1H-indole-6-carboxylic acid. NMR(CD₃OD): δ 2.1(s,3H), 2.3(s,3H), 4.8(s,2H), 7.1-7.2(m,2H),7.4-7.5(m,2H), 7.6-7.7(m,2H), 7.75-7.80(m,1H), 8.5(s,1H).

(n) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 29(m), there was prepared3-methyl-1-(tetrahydrofuran-3-yl)-1H-indole-6-carboxylic acid as a whitesolid, m.p. 211-213° C. [Elemental analysis: C,68.00; H,6.20; N,5.60%.Calculated for C₁₄H₁₅NO₃: C,68.56; H,6.16; N,5.71%].

(o) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 43(a), there was prepared1-benzyl-3-methyl-indazole-6-carboxylic acid.

(p) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 29(o), there was prepared1-(4-methoxybenzyl)-3-methyl-1H-indole-6-carboxylic acid as a whitesolid. NMR (CD₃OD): δ 2.2(s,3H), 3.6(s,3H), 5.2(s,2H), 6.6-6.7(m,2H),6.95-7.0(m,2H), 7.1(s,1H), 7.4-7.45, 7.55-7.60(m,2H), 8.0(s,1H).

(o) By proceeding in a similar manner to Reference Example 28(a) butusing Reference Example 43(b), there was prepared1-(4-methoxybenzyl)-3-methyl-indazole-6-carboxylic acid.

REFERENCE EXAMPLE 29 (a) Methyl1-cyclohexylmethyl-3-methyl-1H-indole-6-carboxylate

A mixture of methyl 3-methyl-1H-indole-6-carboxylate(10 g, ReferenceExample 30), cyclohexylmethylbromide (19 g), potassium hydroxide (12 g)and sodium iodide (0.1 g) in acetone (200 ml) was stirred at roomtemperature for 6 hours. The reaction mixture was evaporated. Theresidue was partitioned between ethyl acetate (250 ml) and water (250ml). The aqueous layer was extracted three times with ethyl acetate (250ml). The total combined organic phases were dried over sodium sulphatethen evaporated. The residue was subjected to flash columnchromatography on silica eluting with a mixture of ethyl acetate andhexane (gradient elution, 0:10 to 1:9, v/v)to yield the title compound(9.5 g). NMR (CDCl₃): δ 0.90-1.10(m), 1.10-1.40(m), 1.60-1.90(m),2.30(s), 3.90-4.00(m), 3.90(s), 7.00(s), 7.50-7.60(m), 7.70-7.80(m),8.00(s). MH⁺ 271.

(b) By proceeding in a similar manner to Reference Example 29(a) butusing (2-cyclohexyl)ethyl bromide there was prepared methyl1-(2-cyclohexyl)ethyl-3-methyl-1H-indole-6-carboxylate. NMR (CDCl₃): δ0.80-1.00(m), 1.10-1.30(m), 1.60-1.80(m), 2.30(s), 3.90(s),4.10-4.20(t), 7.00(s), 7.60(d), 7.80(d), 8.10(s).

(c) By proceeding in a similar manner to Reference Example 29(a) butusing (3-cyclohexyl)propyl bromide there was prepared methyl1-(3-cyclohexyl)propyl-3-methyl-1H-indole-6-carboxylate.

(d) By proceeding in a similar manner to Reference Example 29(a) butusing heptyl bromide there was prepared methyl1-heptyl-3-methyl-1H-indole-6-carboxylate.

(e) By proceeding in a similar manner to Reference Example 29(a) butusing (3-phenyl)butyl bromide there was prepared methyl1-(3-phenyl)butyl-3-methyl-1H-indole-6-carboxylate.

(f) By proceeding in a similar manner to Reference Example 29(a) butusing 4-trifluoromethylbenzyl bromide there was prepared methyl1-(4-trifluoromethylbenzyl)-3-methyl-1H-indole-6-carboxylate as a whitesolid. NMR (CDCl₃): δ 2.30(s); 3.90(s); 5.40(s); 7.00(s); 7.10-7.20(m);7.50-7.60(m); 7.80-7.90(m); 8.00(s).

(g) By proceeding in a similar manner to Reference Example 29(a) butusing 4-methylsulphonylbenzyl bromide there was prepared methyl1-(4-methylsulphonylbenzyl)-3-methyl-1H-indole-6-carboxylate as a whitesolid. NMR (CDCl₃): δ 2.40(s); 3.00(s); 3.90(s); 5.40(s); 7.00(s);7.20-7.30(m); 7.50-7.70(m); 7.80-7.90(m); 8.00(s).

(h) By proceeding in a similar manner to Reference Example 29(a) butusing piperonyl chloride there was prepared methyl1-(1,3-benzodioxol-5-yl)methyl-3-methyl-1H-indole-6-carboxylate.

(i) By proceeding in a similar manner to Reference Example 29(a) butusing (naphthalen-2-yl)methyl chloride there was prepared methyl1-(naphthalen-2-yl)methyl-3-methyl-1H-indole-6-carboxylate.

(j) By proceeding in a similar manner to Reference Example 29(a) butusing (tetrahydro-2H-pyran-2-yl)methyl chloride there was preparedmethyl1-(tetrahydro-2H-pyran-2-yl)methyl-3-methyl-1H-indole-6-carboxylate.

(k) By proceeding in a similar manner to Reference Example 29(a) butusing tetrahydrofurfuryl chloride there was prepared methyl3-methyl-1-(tetrahydrofurfuryl)-1H-indole-6-carboxylate.

(l) By proceeding in a similar manner to Reference Example 29(a) butusing toluene-4-sulphonyl chloride there was prepared methyl3-methyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxylate. NMR (CDCl₃): δ2.2(s,3H), 2.3(s,3H), 4.0(s,3H), 7.15-7.2(m,2H), 7.4-7.5(m,2H),7.7-7.8(m,2H), 7.9-8.0(m,1H), 8.7(s,1H).

(m) By proceeding in a similar manner to Reference Example 29(a) butusing tetrahydrofuran-3-yl chloride there was prepared methyl3-methyl-1-(tetrahydrofuran-3-yl)-1H-indole-6-carboxylate.

(n) By proceeding in a similar manner to Reference Example 29(a) butusing benzyl bromide there was prepared methyl1-benzyl-3-methyl-1H-indole-6-carboxylate as a white solid. NMR (CDCl₃):δ 2.30(s), 3.80(s), 5.20(s), 7.00(s), 7.00-7.10(m), 7.10-7.20(m),7.50-7.60(m), 7.70-7.80(m), 8.00(s).

(o) By proceeding in a similar manner to Reference Example 29(a) butusing 4-methoxybenzyl bromide there was prepared methyl1-(4-methoxybenzyl)-3-methyl-1H-indole-6-carboxylate as a white solid,m.p. 116-118° C. [Elemental analysis: C,73.48; H,6.27; N,4.36%.Calculated for C₁₉H₁₉NO₃: C,73.77; H,6.19; N,4.53%].

REFERENCE EXAMPLE 30 Methyl 3-methyl-1H-indole-6-carboxylate

A mixture of methyl 3-formyl-1H-indole-6-carboxylate (12.0 g),p-toluenesulphonic acid (2.0 g) and p-toluenesulphonylhydrazide (13.0 g)in a mixture of dimethylformamide (100 ml) and sulpholane (50 ml) washeated at 100° C. for 15 minutes and then cooled to room temperature.The mixture was treated with sodium cyanoborohydride (15.0 g, 5 gportions after 10 minute intervals), then heated at 100° C. for 2 hours.After cooling to ambient temperature the reaction mixture was treatedwith ice water (500 ml) giving a white precipitate. Water (1000 ml) wasadded and the mixture stirred for 30 minutes then filtered. Theoff-white solid was washed with warm water then azeotroped with tolueneto yield the title compound (10.2 g) as a white solid.

REFERENCE EXAMPLE 31 (a)1-(6,6-Dimethyl-bicyclo[3.1.1.]hept-3-ylmethyl)-3-methyl-1H-indole-6-carboxylicacid

A mixture of 3-methyl-indole-6-carboxylic acid [1.8 g, Reference Example28(b)], (1S,2S,5S)-(−)-myrtanol tosylate and potassium hydroxide (3.17g) in dimethyl sulphoxide (35 ml) was stirred at room temperature for 18hours. The reaction mixture was partitioned twice between ethyl acetate(25 ml) and dilute hydrochloric acid (25 ml, 1N). The combined organiclayers were dried over sodium sulphate then evaporated. The residue wassubjected to flash chromatography on silica to give the title compound(2.45 g) as a white solid. M⁺325.

(b) By proceeding in a similar manner to Reference Example 31(a) butusing cyclohexanol tosylate there was prepared1-cyclohexyl-3-methyl-1H-indole-6-carboxylic acid as a white solid.

(c) By proceeding in a similar manner to Reference Example 31(a) butusing cyclopentanol tosylate there was prepared1-cyclopentyl-3-methyl-1H-indole-6-carboxylic acid as a white solid. NMR{(CD₃)₂CO }: δ 0.80-0.90(m), 1.20-1.30(m), 1.70-1.90(m), 2.10-2.30(m),2.30(s), 4.90-5.00(m), 7.30(s), 7.50(d), 7.70(d), 8.20(s).

(d) By proceeding in a similar manner to Reference Example 31(a) butusing cycloheptyl methanol tosylate there was prepared1-cycloheptylmethyl-3-methyl-1H-indole-6-carboxylic acid as a whitesolid. NMR {(CD₃)₂CO}: δ 1.10-1.80(m), 2.30(s), 3.30-3.40(m),4.00-4.10(m), 7.30(s), 7.50-7.60(m), 7.70-7.80(m), 8.10(s).

REFERENCE EXAMPLE 32 1-Butyloxycarbonyl-3-methyl-indole-6-carboxylicacid

A stirred solution of 3-methyl-indole-6-carboxylic acid [2.0 g,Reference Example 28(b)]) in dichloromethane (100 ml) was treated withdi-tert-butyl dicarbonate (5.4 g), triethylamine (3.5 ml) and4-dimethylaminopyridine (0.1 g). After stirring at room temperature for4 hours the reaction mixture was evaporated. The residue was partitionedthree times between dichloromethane (100 ml) and water (100 ml). Thecombined organic layers were washed with ice-cold dilute hydrochloricacid (200 ml, 0.1N), then with brine (150 ml), then dried over sodiumsulphate and then evaporated. The residue was subjected to flashchromatography to yield the title compound (2.5 g) as a white solid. NMR{(CD₃)₂SO}: δ 2.30(s), 7.50-7.60(m), 7.80-7.90(s), 8.70(s).

REFERENCE EXAMPLE 33 2-Cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazole-4-yltributyl tin

A solution of 4-bromo-2-cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazole [3.6 g,Reference Example 20(c)] in dry tetrahydrofuran at −70° C. was treatedwith a solution of butyl lithium in hexane (6.8 ml, 1.6M). Afterstirring for 1 hour the mixture was treated with tributyltin chloride(3.07 ml) whilst maintaining the temperature below −70° C., and thereaction mixture was stirred for 1 hour, then allowed to warm to roomtemperature and then left overnight at room temperature. The reactionmixture was quenched with water and then extracted twice with diethylether (100 ml). The combined extracts were dried over magnesium sulphatethen evaporated. The residual yellow oil was subjected to flash columnchromatography on silica eluting with a mixture of ether and pentane(1:1, v/v) to give the title compound as colourless thick oil (3.83 g).

REFERENCE EXAMPLE 34 2-Cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-4-(4-morpholinosulphonyl)-1H(or3H)-benzimidazole

A solution of 2-cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or3H)-benzimidazol-4-ylsulphonyl chloride (0.67 g, Reference example 35)in dichloromethane (16 ml) was treated with pyridine (0.56 ml) andmorpholine (0.15 ml). After stirring at room temperature for 1 hour thenstanding overnight at room temperature the reaction mixture wasevaporated. The residue was azeotroped with toluene to give the titlecompound which was used without further purification.

REFERENCE EXAMPLE 35 2-Cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or3H)-benzimidazole-4-yl-sulphonyl chloride

A solution of 4-bromo-2-cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazole (5.96 g,Reference Example 20(c)]) in dry tetrahydrofuran (80 ml) at −70° C. wastreated dropwise with a solution of butyllithium in hexane (11 ml, 1.6M) whilst maintaining the reaction temperature below −60° C. Afterstirring at this temperature for 1 hour the solution was thentransferred under nitrogen via a cannula to a cooled solution of excesssulphur dioxide in tetrahydrofuran (80 ml) below −60° C. and stirred fora further 30 minutes at −60° C. The reaction mixture was then allowed towarm to room temperature over 1 hour and then evaporated to drynessunder reduced pressure. The residue was triturated with ether to givelithium 2-cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-4-1H(or 3H)-benzimidazolylsulphinate as cream solid (4.82 g). A mixture of this solid anddichloromethane (80 ml), cooled to 0° C. was treated dropwise with asolution of sulphuryl chloride (2 ml) in dichloromethane (20 ml). Afterallowing to warm to room temperature the reaction mixture was evaporatedand the residue was azeotroped with toluene and then triturated withtoluene. The mixture was filtered, the solid was washed with ether. Thecombined filtrate plus washings were evaporated to give the titlecompound as yellow gum (2.2 g).

REFERENCE EXAMPLE 36 5-[2-Cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or3H)-benzimidazole-4-yl]pyridine-2-carboxamide

A solution of 2-cyclopropyl-7-methoxy-1(or3)-(2-trimethylsilanyl-ethoxymethyl)-1H(or 3H)-benzimidazole-4-yltributyl tin (1 g, Reference Example 33) in dimethylformamide (10 ml)was treated with a mixture of 5-bromo-pyridine-2-carboxamide (0.275 g),bis(dibenzylidene)acetone palladium(0) (39.45 mg) and triphenylphosphine(36 mg) in dimethylformamide (1 ml). The mixture was heated at 120° C.under an atmosphere of N₂ for 5 hours then diluted with methanol andthen filtered through a pad of hyflosupercel. The filtrate wasevaporated and the residue was subjected to flash column chromatographyon silica eluting with a mixture of ethyl acetate and pentane (2:8 to1:0, v/v) to give the title compound as cream solid (0.4 g).

REFERENCE EXAMPLE 37 Methyl 1-benzyl-3-methyl-1H-indoline-6-carboxylate

A solution of methyl 1-benzyl-3-methyl-1H-indole-6-carboxylate [0.8 g,Reference Example 29(n)] in trifluoroacetic acid at 0° C. was treatedwith a solution of borane-tetrahydrofuran complex in tetrahydrofuran (9ml, 1M). The solution was kept at 0° C. for 24 hours, then quenched withmethanol, then evaporated. The residual solid was dried under highvacuum and used without purification.

REFERENCE EXAMPLE 38 Methyl3-{3-methyl-1-1-3-(phenyl)propyl}-H-indol-6-yl)-3-nitromethyl-propionate

A stirred solution of methyl3-(3-methyl-1-{3-(phenyl)propyl}-1H-indol-6-yl)-propenoate (0.263 g,Reference Example 39) in nitromethane (5 ml) was treated withtetramethylguanidine (0.091 g). The mixture was heated to 65° C. for 2hours then treated with a further aliquot of tetramethylguanidine (0.091g). After heating at 65° C. for a further hour the reaction mixture wascooled to room temperature then poured into hydrochloric acid (20 ml,1N) then extracted three times with ethyl acetate (25 ml). The combinedextracts were dried over magnesium sulphate then evaporated. The residuewas subjected to preparative layer chromatography on silica using amixture of ethyl acetate and hexane (1:2, v/v) as eluent to yield thetitle compound (0.296 g).

REFERENCE EXAMPLE 39 Methyl3-(3-methyl-1-{3-(phenyl)propyl}-1H-indol-6-yl)-propenoate

A stirred 3-methyl-1-{3-(phenyl)propyl}-1H-indole-6-carboxaldehyde(0.283 g, Reference Example 40) in dry toluene (20 ml), under argon, wastreated with carbomethoxymethylene triphenylphosphorane (0.409 g). Themixture was heated at 80° C. for 4 hours then cooled to room temperatureand then poured into water (20 ml). The organic phase was separated andthe aqueous phase was extracted three times with ethyl acetate (30 ml).The combined organic phases were dried over magnesium sulphate thenevaporated. The residue was subjected to flash chromatography on silicaeluting with a mixture of diethyl ether and hexane (10:1, v/v) to yieldthe title compound (0.263 g).

REFERENCE EXAMPLE 403-methyl-1-{3-(phenyl)propyl}-1H-indole-6-carboxaldehyde

Dimethylsulphoxide (0.311 g) was added to a stirring solution of oxalylchloride in dichloromethane (1 ml, 2M) in dichloromethane (25 ml) at−60° C. under argon and the mixture was stirred for 2 minutes. Asolution of 3-methyl-1-{3-(phenyl)propyl}-1H-indole-6-methanol [0.501 g,Reference Example 22(c)] in dichloromethane (10 ml) was then addeddropwise and the mixture stirred for 15 minutes at −60° C. Triethylamine(0.956 g) was then added and the solution warmed to room temperature andstirred for 1 hour. The mixture was poured into water (20 ml) and thenextracted three times with dichloromethane (25 ml). The combinedextracts were washed with brine (30 ml), then dried over sodium sulphateand then evaporated. The residue was subjected to flash chromatographyon silica eluting with a mixture of ethyl acetate and hexane (1:1, v/v)to yield the title compound (0.283 g).

REFERENCE EXAMPLE 41 Methyl3-methyl-1-{3-(phenyl)propyl}-1H-indole-6-carboxylate

A stirred solution of methyl 3-methyl-1H-indole-6-carboxylate (0.5 g,Reference Example 30) in acetone (35 ml) was treated with1-bromo-3-phenylpropane (0.577 g) and sodium hydroxide (0.116 g). Themixture was stirred at room temperature for 12 hours then poured intowater (35 ml) and then extracted three times with ethyl acetate (50 ml).The combined extracts were washed with dilute hydrochloric acid (50 ml,1N) then with saturated sodium bicarbonate solution (50 ml), then driedover magnesium sulphate and then evaporated. The residue was subjectedto flash column chromatography on silica eluting with a mixture of ethylacetate and hexane (50:1, v/v) to yield the title compound (0.58 g).

REFERENCE EXAMPLE 42 (a) 1-Benzyl-3-methyl-1H-indazole carbonyl chloride

A solution of 1-benzyl-3-methyl-indazole-6-carboxylic acid [0.15 g,Reference Example 28(o)] in dichloromethane (20 ml) was treated withdimethylformamide (2 drops) then with oxalyl chloride (1.69 ml). Afterstirring for 2 hours the reaction mixture was evaporated and the residuewas dried under high vacuum to give the title compound (0.16 g) whichwas used without further purification.

(b) By proceeding in a similar manner to Reference Example 42(a) butusing Reference Example 28(p) there was prepared1-(4-methoxybenzyl)-3-methyl-1H-indole-6-carbonyl chloride.

(c) By proceeding in a similar manner to Reference Example 42(a) butusing Reference Example 26(b) there was prepared4-methoxy-2-methoxymethyl-benzoxazole-6-carbonyl chloride as a paleorange-brown coloured solid.

(d) By proceeding in a similar manner to Reference Example 42(a) butusing Reference Example 26(c) there was prepared3-isopropyl-1-methyl-1H-indole-5-carbonyl chloride.

(e) By proceeding in a similar manner to Reference Example 42(a) butusing Reference Example 28(q) there was prepared1-(4-methoxybenzyl)-3-methyl-1H-indazole-6-carbonyl chloride.

REFERENCE EXAMPLE 43 (a) Methyl1-benzyl-3-methyl-1H-indazole-6-carboxylate

A solution of methyl 3-methyl-indazole-6-carboxylate (0.2 g, ReferenceExample 44) in acetone (15 ml) was treated with benzyl bromide (0.898 g)then with potassium carbonate (0.290 g) and a catalytic amount of18-crown-6. The mixture was stirred for 12 hours at room temperaturethen poured into water (30 ml) and then extracted three times with ethylacetate (30 ml). The combined extracts were dried over sodium sulphatethen evaporated. The residue was subjected to flash chromatography onsilica eluting with a mixture of ethyl acetate and hexane (7:1, v/v) toyield the title compound (0. 161 g) and methyl2-benzyl-3-methyl-indazole-6-carboxylate (0.069 g).

(b) By proceeding in a similar manner to Reference Example 43(a) butusing 4-methoxybenzyl bromide there was prepared methyl1-(4-methoxybenzyl)-3-methyl-indazole-6-carboxylate.

REFERENCE EXAMPLE 44 Methyl 3-methyl-1H-indazole-6-carboxylate

A solution of 3-methyl-indazole-6-carboxylic acid (1.57 g, ReferenceExample 45) in methanol (75 ml) was treated with hydrogen chloride gasfor 10 minutes. The reaction mixture was stirred for 12 hours at roomtemperature then evaporated. The residue was partitioned between ethylacetate (50 ml) and saturated sodium bicarbonate solution (50 ml). Thecombined extracts were dried over sodium sulphate then evaporated. Theresidue was washed with hexane to give the title compound (1.56 g) whichwas used without further purification.

REFERENCE EXAMPLE 45 3-methyl-1H-indazole-6-carboxylic acid

A solution of methyl 1-triflyl-3-methyl-indazole-6-carboxylate(0.668 g,Reference Example 46) in a mixture of methanol and water (3:1, 80 ml)was treated with potassium carbonate (1.15 g). The mixture was heated atreflux for 5 hours then cooled to room temperature then poured into 1Nhydrochloric acid (50 ml). The mixture was extracted three times withethyl acetate (50 ml). The combined extracts were dried over sodiumsulphate then evaporated. The residue was washed with a mixture ofhexane and ether to give the title compound (0.360 g).

REFERENCE EXAMPLE 46 Methyl 1-triflyl-3-methyl-1H-indazole-6-carboxylate

The 6-triflyloxy-1-triflyl-3-methyl-indazole (1.0 g, Reference Example47) was dissolved in dimethylformamide under argon and the solution wasflushed with carbon monoxide for 5 minutes. The solution was treatedwith palladium acetate (0.11 g), diphenylphosphine ferrocene (0.272 g),triethylamine (0.491 g) and methanol (1.56 g) then stirred at roomtemperature for 12 hours under an atmosphere of carbon monoxide. Thereaction mixture was poured into water (150 ml) and the aqueous layerwas extracted three times with ethyl acetate (35 ml). The combinedextracts were dried over sodium sulphate then evaporated. The residuewas subjected to flash chromatography on silica eluting with a mixtureof ethyl acetate and hexane (1:7, v/v) to yield the title compound.

REFERENCE EXAMPLE 47 6-triflyloxy-1-triflyl-3-methyl-1H-indazole

A solution of 6-hydroxy-3-methyl-1H-indazole (0.45 g, Reference Example48) in tetrahydrofuran (30 ml) under argon was treated with sodiumhydride (0.198 g). After the initial effervescence had subsided thesolution was warmed to 50° C. for 1 hour. The reaction mixture wascooled to room temperature and N-phenyltrifluoromethane sulphonimide(2.48 g) was added. The mixture was stirred for 2 hours then poured intowater (50 ml) then extracted three times with ethyl acetate (50 ml). Thecombined extracts were dried over sodium sulphate then evaporated. Theresidue was subjected to flash chromatography on silica eluting with amixture of ethyl acetate and hexane (1:7, v/v) to yield the titlecompound (1.10 g).

REFERENCE EXAMPLE 48 6-hydroxy-3-methyl-1H-indazole

A solution of 6-methoxy-3-methyl-1H-indazole(2.0 g, Reference Example49) in dichloromethane (75 ml) was cooled to 0° C. then treated with asolution of boron tribromide in dichloromethane (54 ml, 1M). The mixturewas allowed to warm to room temperature and then stirred for 12 hours.The solution was poured into an ice-saturated sodium bicarbonate mixtureand the aqueous layer was extracted three times with ethyl acetate (50ml). The combined extracts were dried over sodium sulphate thenevaporated. The residue was subjected to flash chromatography on silicaeluting with a mixture of ethyl acetate and hexane (2:1, v/v) to yieldthe title compound (1.7 g).

REFERENCE EXAMPLE 49 6-methoxy-3-methyl-1H-indazole

2-fluoro-4-methoxyacetophenone (5.0 g) was treated with hydrazine (75ml) under argon and the mixture was heated to reflux for 12 hours. Aftercooling to room temperature, the reaction mixture was poured into water(200 ml) then extracted three times with ethyl acetate (50 ml). Thecombined extracts were dried over sodium sulphate then evaporated. Theresidue was subjected to flash chromatography on silica eluting with amixture of ethyl acetate and hexane (1:3, v/v) to yield the titlecompound (4.05 g).

REFERENCE EXAMPLE 50 5-bromo-2-methoxyaniline

A stirred mixture of 4-bromo-2-nitroanisole (98.56 g) and iron powder(113.7 g) in ethanol (1.51) was heated to reflux and treated dropwisewith hydrochloric acid (350 ml, 0.5N) over 1 hour. After refluxing for afurther 3 hours the reaction mixture was cooled to room temperature thenfiltered through hyflosupercel. The filtrate was evaporated and theresidue was treated with saturated sodium bicarbonate solution (21) thenfiltered. The solid was washed with water then recrystallised fromcyclohexane to give the title compound (61.98 g) as a pale brown solid,m.p. 93-93° C.

REFERENCE EXAMPLE 51 Methyl 2-hydroxy-4-methoxy-3-nitrobenzoate

A solution of methyl 4-methoxysalicylate (50 g) in glacial acetic acid(700 ml) was treated dropwise with concentrated nitric acid (50 ml) over15 minutes. After stirring for 2 hours, then standing at roomtemperature for 18 hours, the mixture was treated with a further aliquotof concentrated nitric acid (10 ml) then stirred for 6 hours. Thereaction mixture was diluted with ice then poured into water (1000 ml),then filtered. The solid was dried then subjected to flashchromatography on silica eluting with a mixture of toluene anddichloromethane (2:1, v/v) to give the title compound as a white solid,m.p. 185-187° C.

REFERENCE EXAMPLE 52 Methyl 3-isopropyl-1H-indole-5-carboxylate

A solution of methyl 3-iodo-4-(3-methyl-but-2-enylamino)-benzoate (2.0g, Reference Example 53) in triethylamine (1.6 ml) and acetonitrile (35ml) was treated with palladium acetate (0.05 g). The mixture was sealedin a bomb and heated at 110° C. for 18 hours. After cooling the reactionmixture was filtered and the filtrate was evaporated. The residue wassubjected to flash chromatography on silica eluting with a mixture ofethyl acetate and petroleum ether (1:4, v/v) to give the title compound(1.0 g).

REFERENCE EXAMPLE 53 Methyl 3-iodo-4-(3-methyl-but-2-enylamino)-benzoate

A solution of diisopropylamine (2.8 ml) in tetrahydrofuran (25 ml),under nitrogen, cooled to −10° C. was treated with butyl lithium inhexane (12.4 ml, 1.6M). The solution was added slowly via a syringe to acooled to solution of methyl 4-amino-3-iodobenzoate (5 g, preparedaccording to the procedure of M. L. Hill, Tetrahedron, 1990, 46, page4587) in tetrahydrofuran (100 ml), under nitrogen and at −78° C. Themixture was allowed to warm to 0° C. and after stirring for a further 10minutes the mixture was cooled to −78° C. and then treated with4-bromo-2-methyl-2-butene (2.49 ml). The reaction mixture was allowed towarm to room temperature over 1.5 hours then poured into saturated brine(100 ml). The organic layer was separated and the aqueous phase wasextracted with ethyl acetate (100 ml). the combined organic phases wereevaporated and the residue was subjected to flash chromatography onsilica eluting with a mixture of ethyl acetate and petroleum ether (1:9,v/v) to give the title compound (5 g).

In Vitro and In Vivo Test Procedures

1. (a) Inhibitory Effects of Compounds on PDE IV Activity

1.1 Preparation of PDE from Guinea Pig Macrophages.

The method is described by Turner et al., Br. J. Pharmacol, 1993, 108,pages 876-883. Briefly, cells are harvested from the peritoneal cavityof horse-serum treated (0.5 ml i.p.) Dunkin Hartley guinea pigs (250-400g) and the macrophages purified by discontinuous (55%, 65%, 70% v/v)gradient (Percoll) centrifugation. Washed macrophages are plated out incell culture flasks and allowed to adhere. The cells are washed withHank's balanced salt solution, scraped from the flasks and centrifuged(1000 g). The supernatant is removed and the pellets stored at −80° C.until use. The pellet is homogenised in 20 mMtris(hydroxymethyl)aminomethane HCl, pH7.5, 2 mM magnesium chloride, 1mM dithiothreitol, 5 mM ethylenediaminetetraacetic acid, 0.25 mMsucrose, 20 mM p-tosyl-L-lycine chloromethyl ketone, 10 mg/ml leupeptinand 2000 U/ml aprotinin.

1.2 Measurement of PDE Activity.

PDE activity is determined in macrophage homogenates by the two-stepradioisotopic method of Thompson et al., Adv. Cyclic Nucl. Res., 1979,10, pages 69-92. The reaction mixture contains 20 mMtris(hydroxymethyl)-aminomethane HCl (pH8.0), 10 mM magnesium chloride,4 mM 2-mercaptoethanol, 0.2 mMethylenebis(oxyethylenenitrilo)-tetraacetic acid and 0.05 mg of bovineserum albumin/mL. The concentration of substrate is 1 μM. The IC₅₀values (i.e. concentrations which produce 50% inhibition of substratehydrolysis) for the compounds examined are determined fromconcentration-response curves in which concentrations range from 0.03 nMto 10 μM.

1.3 Results.

Compounds within the scope of the invention exhibit IC₅₀ values againstguinea pig macrophage cyclic AMP-specific phosphodiesterase (PDE IV) ofbetween 10⁻¹⁰M to about 10⁻⁵M, preferably from about 10⁻¹⁰M up to about10⁻⁶M. The compounds of the invention are from about 10,000-fold toabout 50-fold more selective for cyclic AMP phosphodiesterase IV thancyclic nucleotide phosphodiesterase types I, II, III or V.

(b) Inhibitory Effects of Compounds on PDE V Activity

1.4 Preparation of PDE from Human Platelets.

The method is described by R. E. Weishaar et al., Biochem. Pharmacol.,1986, 35 pages 787-800.

1.5 Measurement of PDE Activity.

PDE activity is determined by the radioisotopic method of Thompson etal., Adv. Cyclic Nucl. Res., 1979, 10, pages 69-92. Following incubationfor 30 minutes at 30° C., [³H]-guanosine 5′-monophosphate is separatedfrom the substrate, guanosine [³H]-guanosine 3′:5′-cyclic monophosphate,by elution on cation-exchange columns, and radioactivity is determinedusing a liquid scintillation counter (LS 1701, Beckman) using liquidscintillation cocktail (Flow Scint III, Packard). The concentration ofsubstrate is 1 μM. The IC₅₀ values for the compounds examined aredetermined from concentration-response curves in which concentrationsrange from 10⁻⁹M to 10⁻⁵M.

2. In Vivo Bronchodilator Actions of Compounds

2.1 Measurement of Bronchodilatation.

Bronchorelaxant activity is measured in in vivo tests in theanaesthetized guinea-pig or rat according to the method described byUnderwood et al., Pulm. Pharmacol., 1992, 5, pages 203-212, in which theeffects on bronchospasm induced by histamine (or other spasmogens suchas methacholine or leukotriene D4) is determined. Compounds areadministered orally 1 hour prior to administration of spasmogen.

3. In Vivo Actions of Compounds on Antigen (Ovalbamin)-InducedEosinophilia in Guinea-Pigs

3.1 Treatment of Animals and Measurement of Eosinophil Numbers.

Male Dunkin-Hartley guinea-pigs weighing 200-250 g are sensitized using10 μg ovalbumin in 1 mL of a 100 mg/mL suspension of aluminiumhydroxide, i.p.

28 days after sensitization guinea-pigs are dosed orally. 23 Hours laterthis procedure is repeated and 60 minutes later the guinea-pigs arechallenged with nebulised saline or ovalbumin (1% in saline) for 15seconds. 24 Hours after challenge the guinea-pigs are killed and thelungs are lavaged with warm saline. Total and differential cell countsare made.

4. Inhibitory Effects of Compounds Against Antigen-Induced Eosinophiliain the Rat In Vivo

4.1. Treatment of Rats and Measurement of Eosinophil Numbers.

Male Brown Norway rats weighing 150-250 g are sensitized on days 0, 12and 21 with ovalbumin (100 μg, i.p.). Rats are challenged on any one daybetween days 27-32. 24 hours and 1 hour before antigen challenge thetest compound is orally dosed. Rats are challenged by exposure for 30minutes to nebulized saline or ovalbumin (1% in saline). 24 hours afterchallenge, rats are killed and the airways are lavaged with RPMI and 10%foetal calf serum. Total and differential cell counts are made.

5. In Vitro Inhibitory Effects on TNF-Alpha Release by Human Monocytes

The effects of compounds on TNF-alpha production by human peripheralblood monocytes (PBMs) are examined as follows.

5.1. Preparation of Blood Monocytes.

Blood is drawn from normal donors into sodium citrate (3.8%) as ananticoagulant. Mononuclear cells are fractionated by centrifugationthrough a histopaque gradient system (Accuspin, Sigma, U.K.). Themonouclear cell fraction comprising 90% mononuclear cells (contaminatingcells being neutrophils), is suspended in Hanks balanced salt solution(HBSS), (Life Technologies Ltd U.K.) containing 1% v/v Human serumalbumin (HSA) (Sigma U.K.). The cells are washed, counted andresuspended at 10⁶ cells/ml in RPMI 1640 tissue culture mediumcontaining 1% v/v foetal calf serum (FCS), 50 U/ml penicillin, 50 mg/mlstreptomycin (Life Technologies Ltd), then plated out in 96 well platesat 2×10⁶ cells/well.

5.2. TNF-Alpha Release.

Following 2 hours incubation (37° C., 5% CO₂) medium and non adherentcells are removed leaving pure adherent monocytes. RPMI (200 μl) mediumis replaced with that containing compounds for evaluation, or vehicle.Control treatments and compounds for test are assayed in quadruplicatewells. Compounds are tested within the concentration range 10⁻¹⁰-10⁻⁵ M,and allowed to incubate with the cells for 1 hour. LPS (E. coli 055:B5Sigma, U.K.) is added in RPMI to give a final concentration of 10 ng/mland the incubation is continued for a further 18 hours.

5.3. TNF-Alpha Measurement.

Cell supernatants are removed and assayed for TNF-alpha by sandwichELISA as follows.

ELISA plates (Costar, U.K.) are coated overnight at 4° C. with 2.5 μg/mlpolyclonal goat anti-human TNF-alpha antibody (R&D Systems, U.K.) in pH9.9 bicarbonate buffer. Polyclonal rabbit anti-human TNF-alpha antibody(Endogen, U.S.A.) is used as the second antibody (2.5 μg/ml) andpolyclonal goat anti-rabbit IgG-horseradish peroxidase (Calbiochem,U.K.) is used as the detection antibody (1:8000 dilution).

Colour development following addition of the substratetetramethybenzidine (TMB) solution (Sigma, U.K.) is measured byabsorbance at 450 nm using a Titertek plate reader (ICN, U.K.).

TNF-alpha levels are calculated by interpolation from a standard curveusing recombinant human TNF-alpha (R&D Systems) (0.125-16 ng/ml). Dataare fitted by linear regression using GraphPad PRIZM v 2.01 software.Basal TNF-alpha levels are less than 100 pg/ml whilst LPS stimulation ofmonocytes increases TNF-alpha levels to 5-10 ng/ml.

5.4. Results.

Compounds within the scope of the invention produce 50% inhibition ofLPS induced TNF-alpha release from human monocytes at concentrationswithin the range of about 10⁻⁹M-10⁻⁶M, preferably about 10⁻⁹M -10⁻⁷M.

6. Inhibitory Effects of Compounds on Antigen-InducedBronchoconstriction in the Conscious Guinea-Pig

6.1 Sensitisation of Guinea-Pigs and Measurement of Antigen-InducedBronchoconstriction.

Male Dunkin-Hartley guinea-pigs (550-700 g) are sensitized as above.Specific airways resistance (SRaw) is measured in conscious animals bywhole body plethysmography using a variation of the method of Pennocket. al. J. Appl. Physiol., 1979, 46, 399). Test compounds or vehicle areadministered orally 24 hours and 1 hour before antigen challenge. 30Minutes before challenge the animals are injected with mepyramine (30mg/kg i.p.) to prevent anaphyl-actic collapse and placed into theplethysmography chambers where SRaw is determined at 1 minute intervals.Resting SRaw is then determined. Animals are challenged with an aerosolof ovalbumin and SRaw is determined every 5 minutes for 15 minutes.

7. Inhibitory Effects of Compounds Against Antigen-InducedBronchoconstriction in the Anaesthetized Rat In Vivo

7.1. Treatment of Rats and Measurement of Antigen-InducedBronchoconstriction.

Male Brown Norway rats weighing 150-250 g are sensitized on days 0, 12and 21 with ovalbumin (100 μg, i.p.). Rats are challenged on any one daybetween days 27-32. 24 hours and 1 hour before antigen challenge thetest compounds are orally dosed. Rats are anaesthetized to allowrecording of lung function (airway resistance and lung compliance) usingrespiratory mechanics software. Rats are challenged with ovalbumin i.v.and the peak changes in airway resistance and lung compliance aredetermined.

7.2 Results.

Compounds within the scope of the invention inhibit antigen-inducedbronchoconstriction by up to 89% at doses of 10 mg/kg.

8. Inhibitory Effects of Compounds on Serum TNF-Alpha Levels inLPS-Challenged Mice

8.1. Treatment of Animals and Measurement of Murine TNF-Alpha.

Female Balb/c mice (age 6-8 weeks, weight 20-22 g) are orally dosed withthe test compound. After a minimum of 30 minutes they are challengedi.p. with 30 μg of LPS per mouse. After 90 minutes the animals arekilled by carbon dioxide asphyxiation and bled by cardiac puncture.Blood is allowed to clot at 4° C., centrifuged (385 g for 5 minutes) andserum taken for TNF-alpha analysis. TNF-alpha levels are measured usinga commercially available murine TNF-alpha ELISA kit, purchased fromGenzyme (Cat. no. 1509.00), as recommended by the manufacturer. Valuesfor TNF-alpha are calculated from a recombinant murine TNF-alphastandard curve.

9. Systemic Bioavailability in Female Balb/c Mouse

Intravenous Administration:

Following surgery to expose the jugular vein for dosing, a solution oftest compound in dimethylsulphoxide is added at a dose of 1 mg/kg bodyweight.

Oral Administration:

A suspension of test compound in 1.5% aqueous carboxymethylcellulose isintroduced into the stomach by gavage at a dose of 1 mg/kg body weight.Following either i.v. or oral dosing, blood is obtained by cardiacpuncture following carbon dioxide asphyxiation and is obtained at asingle time post-dose for each animal. Three animals are sacrificed ateach time point. Blood samples are obtained at the following times afterdosing by both the i.v. and oral routes; 5 minutes (i.v. only), 0.25,0.5, 1, 2, 3, 4, 5.5, 7 and 24 hours. Corresponding plasma is obtainedby centrifugation of each blood sample. The drug content in the plasmasamples is then determined using conventional methods.

9.1 Metabolism

(i)Preparation of Mouse Liver Homogenate.

Fresh mouse liver is homogenised in sucrose-phosphate buffer. Followingcentrifugation the resulting supernatant (liver homogenate) is usedfresh or frozen in liquid nitrogen for one minute and stored at −30° C.to −40° C. prior to use.

(ii) Incubation of Compounds with Mouse Liver Homogenate.

To 0.5 ml of mouse liver homogenate is added 0.5 ml taken from avortexed mixture of 8 mg NADPH added to a mixture of aqueous magnesiumchloride (1 ml, 0.15M) nicotinamide (1 ml, 0.5M) and pH 7.4 tris buffer(8.5 ml, 0.1M). The compound is added at a concentration of 1 μg/ml in10 μl of solvent. Incubates are maintained at 37° C. Samples are takenat 0 minutes, 5 minutes, 10 minutes, 20 minutes and 30 minutes and theincubation stopped by the addition of 100 μl acetonitrile. The drugcontent in the incubation samples is determined using conventionalmethods.

10. Streptococcal Cell Wall-Induced Arthritis in Rats

10.1 Preparation of S. pyogenes Purified Cell Wall

Purified S. pyogenes cell wall is prepared from the cell pellet of alog-phase culture of S. pyogenes, group A, strain D-58. The wholebacteria are homogenized by grinding with glass beads and the crude cellwall collected by centrifugation and subsequently washed with 2% sodiumdodecyl sulphate in phosphate buffered saline followed by phosphatebuffered saline to remove contaminating proteins and nucleic acids. Thecell wall is further purified by sonication and differentialcentrifugation to obtain a purified preparation which pelleted at100,000 g. This material is suspended in sterile phosphate bufferedsaline and the quantity of cell wall determined by measuring therhamnose content of the preparation (purified cell wall contains 28%rhamnose by weight). The material is filtered through a 0.22 μM filterand stored at 4° C. until used for arthritis induction.

10.2 Arthritis Induction and Measurement of Joint Diameters.

Female Lewis rats weighing 140-160 g are injected intra-articularly intothe left or right tibio-tarsal joint of one hind leg on day 0 withpurified S. pyogenes cell wall extract (10 mg in 10 ml sterile saline).On day 20, rats received an intravenous injection of purified cell wall(100 μg in 100 μl sterile saline) via the lateral vein of the tail.Joint diameters are measured with calipers across the lateral and medialmalleoli of the previously intra-articularly injected joint immediatelyprior to the i.v. injection and then daily through day 24. The net jointdiameter is determined by subtracting the value for the contralateraljoint. Body weights are also measured daily. Compounds or vehicle areadministered by oral gavage on days 20-23. Typically, 8-10 animals areused per group. For each dose, the total daily dose is divided into twoequal aliquots which are given at approximately 9 a.m. and 3 p.m.

1. A compound of the general formula (I):

wherein

represents a bicyclic ring system, of about 10 to about 13 ring members,in which the ring

is an azaheterocycle, and the ring

represents an azaheteroaryl ring, or an optionally halo substitutedbenzene ring; R¹ represents hydrogen or a straight- or branched-chainalkyl group of 1 to about 4 carbon atoms, optionally substituted byhydroxy or one or more halogen atoms, or when Z¹ represents a directbond R¹ may also represent a lower alkenyl or lower alkynyl group, or aformyl group; R² represents hydrogen, alkenyl, alkoxy, alkyl,alkylsulphinyl, alkylsulphonyl, alkylthio, aryl, arylalkyloxy,arylalkylsulphinyl, arylalkylsulphonyl, arylalkylthio, aryloxy,arylsulphinyl, arylsulphonyl, arylthio, cyano, cycloalkenyl,cycloalkenyloxy, cycloalkyl, cycloalkyloxy, heteroaryl,heteroarylalkyloxy, heteroaryloxy, hydroxy, —SO₂NR⁴R⁵, —NR⁴SO₂R⁵,—NR⁴R⁵, —C(═O)R⁵, —C(═O)C(═O)R⁵, —C(═O)NR⁴R⁵, —C(═O)OR⁵, —O(C═O)NR⁴R⁵,or —NR⁴C(═O)R⁵; R³ represents a group selected from: (i) —C(=Z)—N(R⁷)R⁶(ii) —C(=Z)—CHR¹²R⁶ (iii) —C(=Z)—R⁶ (iv) —CR⁸═C(R⁹)(CH₂)_(p)—R⁶ (v)—C(R¹⁰)═C(R¹¹)R¹² (vi) —C(R¹³)(R¹⁰)C(R¹¹)(R¹⁴)R¹² (vii)—C(R⁸)(R¹⁵)CH(R⁹)(CH₂)_(p)—R⁶ (viii) —R⁶ (ix) —N(R¹⁶)C(=Z)R⁶ (x)—C(R¹⁷)═N—OC(=0)R¹⁸ (xi) —C(═O)—N(R¹⁹)OR²⁰ (xii) —C≡C—R⁶ (xiii)—CH₂—C(=Z)—R⁶ (xiv) —C(=Z)—C(=Z)R⁶ (xv) —CH₂—NHR⁶ (xvi) —CH₂-ZR⁶ (xvii)—CH₂—SOR⁶ (xviii) —CH₂—SO₂R⁶ (xix) —CF₂—OR⁶ (xx) —NH—CH₂R⁶ (xxi)-Z-CH₂R⁶ (xxii) —SO—CH₂R⁶ (xxiv) —SO₂—CH₂R⁶ (xxv) —O—CF₂R⁶ (xxiii)—O—C(=Z)R⁶ (xxvi) —N═N—R⁶ (xxvii) —NH—SO₂R⁶ (xxviii) —SO₂—NR²¹R²² (xxix)—CZ-CZ-NHR⁶ (xxx) —NH—CO—OR⁶ (xxxi) —O—CO—NHR⁶ (xxxii) —NH—CO—NHR⁶(xxxiii) —R²³ (xxxiv) —CX¹═CX²R⁶ (xxxv) —C(═NOR²⁴)—(CH₂)_(q)R⁶ (xxxvi)—CH₂—CO—NH(CH₂)_(q)R⁶ (xxxvii) —CH₂—NH—CO(CH₂)_(q)R⁶ (xxxviii)—CH₂—CO—CH₂R⁶ (xxxix) —C(═NR²⁵)—NH(CH₂)_(q)R⁶ (xxxx)—C(X³)═N—(CH₂)_(q)R⁶ (xxxxi) —CH(X⁴)—CH₂R⁶ where: R⁴ and R⁵, which maybe the same or different, each represent a hydrogen atom, or an alkyl,aryl, arylalkyl, cycloalkyl, heteroaryl, or heteroarylalkyl group; R⁶ isaryl or heteroaryl; R⁷ is a hydrogen atom or an alkyl or amino group; R⁸and R⁹, which may be the same or different, is each a hydrogen atom oralkyl, —CO₂R⁵, —C(=Z)NR²⁶R²⁷ (where R²⁶ and R²⁷ may be the same ordifferent and each is as described for R⁵), —CN or —CH₂CN; R¹⁰ and R¹¹,which may be the same or different, is each a group —(CH₂)_(p)R⁶; R¹² isa hydrogen atom or an alkyl group; R¹³ is a hydrogen or halogen atom oran —OR²⁸ group (where R²⁸ is a hydrogen atom or an alkyl, alkenyl,alkoxyalkyl, acyl, carboxamido or thiocarboxamido group); R¹⁴ is ahydrogen atom or an alkyl group; R¹⁵ is a hydrogen atom or a hydroxylgroup; R¹⁶ is a hydrogen atom or an alkyl, amino, aryl, arylalkyl orhydroxy group; R¹⁷ is a hydrogen atom or a C₁₋₄alkyl or arylC₁₋₄alkylgroup; R¹⁸ is an amino, alkylamino, arylamino, alkoxy or aryloxy group;R¹⁹ is an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group;R²⁰ is R⁵, (CH₂)_(p)CO₂R⁵ or (CH₂)_(p)COR⁵; R²¹ is a group -L¹-R²⁹, orR²¹ is an optionally substituted cycloalkyl, cycloalkenyl orheterocycloalkyl group which may optionally be fused to an additionaloptionally substituted aromatic, heteroaromatic, carbocyclic orheterocycloalkyl ring (where the one or more optional substituents, foreither or both rings, may be represented by -L¹-R²⁹); L¹ is a straightor branched C₁₋₆alkylene chain, a straight or branched C₂₋₆alkenylenechain, a straight or branched C₂₋₆alkynylene chain or a straight orbranched C₁₋₆alkylene chain containing an oxygen or sulphur atom, aphenylene, imino (—NH—) or alkylimino linkage, or a sulphinyl orsulphonyl group, in which each of the alkylene, alkenylene andalkynylene chains may be optionally substituted, the substituents chosenfrom alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen, heteroaryl,hydroxyl or oxo; and R²⁹ is hydrogen, or arylalkoxycarbonyl, carboxy oran acid bioisostere, cyano, —NY¹Y²; Y¹ and Y² are independentlyhydrogen, alkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl, or the group —NY¹Y² may form a 4-6 membered cyclicamine (which ay optionally contain a further heteroatom selected from O,S, or NY¹, or which may be fused to an additional aromatic orheteroaromatic ring); R²² is a hydrogen atom, a group -L¹-R²⁹, or anoptionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl orheterocycloalkyl group which may optionally be fused to an additionaloptionally substituted aromatic, heteroaromatic, carbocyclic orheterocycloalkyl ring (where the one or more optional substituents, foreither or both rings, may be represented by -L¹-R²⁹); or both R²¹ andR²² represent aryl or heteroaryl each optionally substituted by -L¹-R²⁹;or the group —NR²¹R²² represents an optionally substituted, saturated orunsaturated 3 to 8 membered cyclic amine ring, which may optionallycontain one or more heteroatoms selected from O, S or N, and may also befused to an additional optionally substituted aromatic, heteroaromatic,carbocyclic or heterocycloalkyl ring (where the one or more optionalsubstituents, for any of the rings, may be represented by -L¹-R²⁹);

where: R³⁰ is a hydrogen atom or an alkyl, hydroxyalkyl or alkoxyalkylgroup; R³¹ is a hydrogen atom or an alkyl, carboxy, CONHOR¹⁴,N-alkylaminoalkyl, N,N-dialkylaminoalkyl or alkoxyalkyl group; or R³⁰and R³¹ together represent a —CH₂—O—CH_(2—O—CH) ₂— group; R³² is ahydrogen atom, or amino, alkyl, aminoalkyl, hydroxyalkyl, hydroxy, acyl,alkoxycarbonyl, methoxycarbonylalkyl, —(CH₂)_(p)CONY³Y⁴; Y³ and Y⁴ areeach independently hydrogen or alkyl; —(CH₂)_(p)SO₂NY³Y⁴,—(CH₂)_(p)PO₃H₂, —(CH₂)_(p)SO₂NHCOalkyl, or —(CH₂)_(p)SO₂NHCOR⁶; R³³ isC₁₋₄alkyl, CH₂NHCOCONH₂, CH═C(R⁴³)R⁴⁴, cyclopropyl (optionallysubstituted by R⁴³), CN, CH₂OR⁴⁴ or CH₂NR⁴⁴R⁴⁵; R⁴³ is R⁴⁴ or fluorineand R⁴⁴ is hydrogen or C₁₋₄alkyl optionally substituted by 1 to 3fluorine atoms; R⁴⁵ is hydrogen, OR⁴⁴, or C₁₋₄alkyl optionallysubstituted by 1 to 3 fluorine atoms; NR⁴⁴R⁴⁵ represents a 5 to 7membered cyclic amine optionally containing one or more additionalheteroatom selected from O, N, or S; R³⁴ is methyl or ethyl optionallysubstituted by 1 or more halogen atoms; R³⁵ is R¹⁴, —OR¹⁴, —CO₂R¹⁴,—COR¹⁴, —CN, —CONY³Y⁴ or —NY³Y^(4;) R³⁶ is —C(=Z)R¹⁴, —CO₂R¹⁴, —CONY³Y⁴or —CN; R³⁷ and R³⁹, which may be the same or different, is each ahydrogen atom, alkyl, acyl, arylalkyl, —(CH₂)_(p)CO₂R⁵, —CONHR⁵,heteroarylalkyl, aryl, or heteroaryl; R³⁸ is acyl, aroyl,—C(═O)cycloalkyl, alkoxycarbonyl, cycloalkoxycarbonyl, carboxy,alkoxyalkyl, —NO₂, —CH₂OH, —CN, —NR¹⁴COR⁵, —NR¹⁴CONY⁵Y⁶, —NR¹⁴SO₂R⁴⁶,—SO₂R⁴⁶ or —CONY⁵Y⁶; R⁴⁶ is alkyl, cycloalkyl, trifluoromethyl, aryl,arylalkyl or —NY⁵Y⁶; Y⁵ and Y⁶ are independently selected from hydrogen,alkyl, cycloalkyl, aryl or arylalkyl, or Y⁵ and Y⁶ together form a 4- to7-membered heterocyclic or carbocyclic ring; R⁴⁰ is hydrogen, alkyl,haloalkyl, cycloalkyl, aryl, acyl, aroyl, —C(═O)cycloalkyl, —CH₂OH,alkoxyalkyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, —CN,—NO₂, or —SO₂R⁴⁶; R⁴¹ is —CN, —C(Z)R⁴⁷ (where R⁴⁷ is hydrogen, alkyl,haloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, C₁₋₆alkoxy,arylalkoxy, aryloxy or —NY⁵Y⁶) or SO₂R⁴⁶; R⁴² is hydrogen, alkyl,cycloalkyl, acyl, aroyl, —C(═O)cycloalkyl, alkoxycarbonyl,cycloalkoxycarbonyl, carboxy, —CN, —SO₂R⁴⁶ or —CONY⁵Y⁶; W is (CH₂)_(r)or NR³⁹; Z³ is an oxygen atom, NR¹⁴ or NOR¹⁴; s is zero or an integer 1to 4; r is 1 to 4; and Y is an oxygen atom, C(═O), CH(OH) orC(OR¹⁴)(CH₂)_(p)R⁶; R²⁴ is R⁵ or CONHR²⁵; R²⁵ is hydrogen, C₁₋₃alkyl or(CH₂)_(q)R⁶; p is zero or an integer 1 to 5; q is zero or 1; X¹ and X²,which may be the same or different, is each a hydrogen or fluorine atom;X³ is a chlorine or fluorine atom, alkoxy, aryloxy, heteroaryloxy,arylalkyloxy or heteroarylalkyl; X⁴ is a halogen atom or hydroxy; Zrepresents an oxygen or sulphur atom; A¹ represents a direct bond, or astraight or branched C₁₋₆alkylene chain optionally substituted byhydroxyl, alkoxy, oxo, cycloalkyl, aryl or heteroaryl, or A¹ representsa straight or branched C₂₋₆alkenylene or C₂₋₆alkynylene chain; Z¹represents a direct bond, an oxygen or sulphur atom or NH; n and m eachrepresent zero or 1, provided that n is 1 when m is zero and n is zerowhen m is 1; and N-oxides thereof, and their prodrugs, andpharmaceutically acceptable salts and solvates of the compounds offormula (I) and N-oxides thereof, and their prodrugs.
 2. The compoundaccording to claim 1 in which R¹ represents C₁₋₄alkyl optionallysubstituted by one or more halogen atoms.
 3. The compound according toclaim 1 in which Z¹ represents a direct bond or an oxygen atom.
 4. Thecompound according to claim 1 in which A¹ represents a direct bond or astraight- or branched-chain alkylene linkage containing from 1 to 6carbon atoms and optionally substituted by alkoxy.
 5. The compoundaccording to claim 1 in which R³ represents —C(═O)NHR⁶, —C(═O)CH₂R⁶ or—OCH₂R⁶ wherein R⁶ is an optionally substituted azaheteroaryl group. 6.The compound according to claim 5 in which R⁶ is pyridyl or isoxazolylsubstituted on both positions adjacent to the position of attachment ofR⁶ to the rest of the molecule.
 7. The compound according to claim 5 inwhich R⁶ is pyridyl or isoxazolyl substituted by two methyl or halogenmoieties on both positions adjacent to the position of attachment of R⁶to the rest of the molecule.
 8. The compound according to claim 5 inwhich R⁶ is 3,5-dimethylpyrid-4-yl, 3,5-dihalopyrid-4-yl or an N-oxideof such groups.
 9. The compound according to claim 5 in which R⁶ is3,5-dimethylisoxazol-4-yl.
 10. The compound according to claim 1 inwhich ring

represents a 5-membered azaheterocycle containing at least one nitrogenatom, and ring

represents a 6-membered azaheteroaryl or a benzene ring.
 11. A compoundof formula (Ia)

wherein R¹, R², R³, A¹ and Z¹ are as defined in claim 1, Q¹ is CH, CX⁵(where X⁵ is halogen), a nitrogen atom or N⁺—O⁻ and

(where R⁵ represents a hydrogen atom or a methyl group), and N-oxidesthereof, and their prodrugs, and pharmaceutically acceptable salts andsolvates of the compounds of formula (I) and N-oxides thereof and theirprodrugs.
 12. The compound according to claim 11 in which R¹ representsC₁₋₄alkyl optionally substituted by one or more halogen atoms.
 13. Thecompound according to claim 11 in which R¹ represents methyl ordifluoromethyl.
 14. The compound according to claim 11 in which R²represents a straight- or branched-chain C₁₋₄alkyl group, or cycloalkyl,alkoxy, aryl, aryloxy or heteroaryl.
 15. The compound according to claim11 in which R³ represents —C(═O)—NHR⁶, —C(═O)—CH₂R⁶ or —O—CH₂R⁶ (whereR⁶ represents a disubstituted azaheteroaryl group, or an N-oxidethereof).
 16. The compound according to claim 15 in which R⁶ is pyridylor isoxazolyl substituted on both positions adjacent to the position ofattachment of R⁶ to the rest of the molecule.
 17. The compound accordingto claim 15 in which R⁶ is pyridyl or isoxazolyl substituted by twomethyl or halogen moieties on both positions adjacent to the position ofattachment of R⁶ to the rest of the molecule.
 18. The compound accordingto claim 15 in which R⁶ is 3,5-dimethylpyrid-4-yl, 3,5-dihalopyrid-4-ylor an N-oxide of such groups.
 19. The compound according to claim 15 inwhich R⁶ is 3,5-dimethylisoxazol-4-yl.
 20. The compound according toclaim 11 in which A¹ represents a direct bond or a straight- orbranched-chain alkylene linkage containing 1 to 6 carbon atomsoptionally substituted by alkoxy.
 21. The compound according to claim 11in which

and where R⁵ is a hydrogen atom.
 22. The compound according to claim 11in which Q¹ is a CH linkage.
 23. The compound according claim 11 inwhich Z¹ is an oxygen atom.
 24. The compound according to claim 11 inwhich R¹ is methyl or difluoromethyl, R² is C₁₋₄alkyl, C₃₋₆cycloalkyl,C₁₋₄alkoxy, aryl, aryloxy or azaheteroaryl, R³ is —C(═O)—NHR⁶,—C(═O)—CH₂R⁶ or —O—CH₂R⁶ (where R⁶ is a dimethyl- ordihalo-azaheteroaryl), A¹ is a direct bond or a methylene linkage;

Q¹ is a CH linkage and Z¹ is an oxygen atom, and N-oxides thereof, andtheir prodrugs, and pharmaceutically acceptable salts and solvates ofthe compounds of formula (Ia) herein and N-oxides thereof, and theirprodrugs.
 25. A compound of formula (Ib)

wherein R¹, R², R³, A¹ and Z¹ are as defined in claim 1, and Qrepresents a CH linkage or a nitrogen atom, and N-oxides thereof, andtheir prodrugs, and pharmaceutically acceptable salts and solvates ofthe compounds of formula (Ib) and N-oxides thereof, and their prodrugs.26. The compound according to claim 25 in which R¹ is hydrogen ormethyl, R² is C₄₋₉alkyl, C₃₋₇cycloalkyl, aryl, heteroaryl orheterocycloalkyl, R³ is —C(═O)—NHR⁶, —C(═O)—CH₂R⁶ or —O—CH₂R⁶ (where R⁶is a dimethyl- or dihalo-azaheteroaryl), A¹ is a direct bond or amethylene linkage, Z¹ is a direct bond, and Q is a CH linkage or anitrogen atom, and N-oxides thereof, and their prodrugs, andpharmaceutically acceptable salts and solvates of the compounds offormula (Ib) herein and N-oxides thereof, and their prodrugs.
 27. Acompound of formula (Ic)

wherein R¹, R², R³, A¹ and Z¹ are as defined in claim 1, Q¹ is CH, CX⁵(where X⁵ is halogen), a nitrogen atom or N⁺—O⁻ and Z is an oxygen orsulphur atom, and N-oxides thereof, and their prodrugs, andpharmaceutically acceptable salts and solvates of the compounds offormula (Ic) and N-oxides thereof, and their prodrugs.
 28. The compoundaccording to claim 27 in which R¹ is methyl or difluoromethyl, R² isC₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy, aryl, aryloxy or azaheteroaryl,R³ is —C(═O)—NHR⁶, —C(═O)—CH₂R⁶ or —O—CH₂R⁶ (where R⁶ is a dimethyl- ordihalo-azaheteroaryl), A¹ is a direct bond or a methylene linkage, Q¹ isa CH linkage, and Z and Z¹ are both oxygen atoms, and N-oxides thereof,and their prodrugs, and pharmaceutically acceptable salts and solvatesof the compounds of formula (Ic) herein and N-oxides thereof, and theirprodrugs.
 29. A compound of formula (Id)

wherein R¹, R², R³, A¹ and Z¹ are as defined in claim 1, Q¹ is CH, CX⁵(where X⁵ is halogen), a nitrogen atom or N⁺—O⁻ and Z is an oxygen orsulphur atom, and N-oxides thereof, and their prodrugs, andpharmaceutically acceptable salts and solvates of the compounds offormula (Id) and N-oxides thereof, and their prodrugs.
 30. The compoundaccording to claim 29 in which R¹ is methyl or difluoromethyl, R² isC₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy, aryl, aryloxy or azaheteroaryl,R³ is —C(═O)—NHR⁶, —C(═O)—CH₂R⁶ or —O—CH₂R⁶ (where R⁶ is a dimethyl- ordihalo-azaheteroaryl), A¹ is a direct bond or a methylene linkage, Q¹ isa CH linkage, and Z and Z¹ are both oxygen atoms, and N-oxides thereof,and their prodrugs, and pharmaceutically acceptable salts and solvatesof the compounds of formula (Id) herein and N-oxides thereof, and theirprodrugs.
 31. A compound of formula (Ie)

wherein R¹, R², R³, A¹ and Z¹ are as defined in claim 1, and N-oxidesthereof, and their prodrugs, and pharmaceutically acceptable salts andsolvates of the compounds of formula (Ie) and N-oxides thereof, andtheir prodrugs.
 32. The compound according to claim 31 in which R¹ ishydrogen or methyl, R² is C₄₋₉alkyl, C₃₋₇cycloalkyl, aryl, heteroaryl orheterocycloalkyl, R³ is —C(═O)—NHR⁶, —C(═O)—CH₂R⁶ or —O—CH₂R⁶ (where R⁶is a dimethyl- or dihalo-azaheteroaryl), A¹ is a direct bond or amethylene linkage and Z¹ is a direct bond, and N-oxides thereof, andtheir prodrugs, and pharmaceutically acceptable salts and solvates ofthe compounds of formula (Ie) herein and N-oxides thereof, and theirprodrugs.
 33. A compound of formula (If)

wherein R¹, R², R³, A¹ and Z¹ are as defined in claim 1, and N-oxidesthereof, and their prodrugs, and pharmaceutically acceptable salts andsolvates of the compounds of formula (If) and N-oxides thereof, andtheir prodrugs.
 34. The compound according to claim 33 in which R¹ ishydrogen or methyl, R² is C₁₋₄alkyl, C₃₋₇cycloalkyl, aryl, heteroaryl orheterocycloalkyl, R³ is —C(═O)—NHR⁶, —C(═O)—CH₂R⁶ or —O—CH₂R⁶ (where R⁶is dimethyl- or dihalo-azaheteroaryl), A¹ is a direct bond or amethylene linkage and Z¹ is an oxygen atom, and N-oxides thereof, andtheir prodrugs, and pharmaceutically acceptable salts and solvates ofthe compounds of formula (If) herein and N-oxides thereof, and theirprodrugs.
 35. A compound according to claim 1 selected from the groupconsisting of:N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenyl-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenethyl-3H-benzimidazole-4-carboxamide;2-benzyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;(RS)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxamide;(R)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxamide;(S)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylethyl)-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxy-benzyl)-3H-benzimidazole-4-carboxamide;(RS)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;(R)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;(S)-2-(cyclohexyl-phenyl-methyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;(RS)—N-(3,5-dichloro-4-pyridyl)-2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxamide;(R)—N-(3,5-dichloro-4-pyridyl)-2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxamide;(S)—N-(3,5-dichloro-4-pyridyl)-2-(1,2-diphenylethyl)-7-methoxy-3H-benzimidazole-4-carboxamide;(RS)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-phenylpropyl)-3H-benzimidazole-4-carboxamide;(R)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-phenylpropyl)-3H-benzimidazole-4-carboxamide;(S)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-phenylpropyl)-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxyphenoxymethyl)-3H-benzimidazole-4-carboxamide;(RS)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxamide;(R)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxamide;(S)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(1-phenylbutyl)-3H-benzimidazole-4-carboxamide;2-(4-bromobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;(RS)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[3-methoxy-1-phenylpropyl]-3H-benzimidazole-4-carboxamide;(R)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[3-methoxy-1-phenylpropyl]-3H-benzimidazole-4-carboxamide;(S)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[3-methoxy-1-phenylpropyl]-3H-benzimidazole-4-carboxamide;2-(4-cyanobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-[4-(3-pyridyl)benzyl]-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-methoxy-benzyl)-3H-benzimidazole-4-carboxamide;(RS)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(methoxy-phenyl)methyl-3H-benzimidazole-4-carboxamide;(R)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxy-phenyl)methyl-3H-benzimidazole-4-carboxamide;(S)—N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(4-methoxy-phenyl)methyl-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(2-methoxyphenoxy)methyl-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-(3-pyridyl)-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-2-isopropyl-7-methoxy-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methyl-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-phenoxymethyl-3H-benzimidazole-4-carboxamide;2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;2-benzyl-N-(3,5-dichloro-4-pyridyl)-3H-benzimidazole-4-carboxamide;2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-1-methyl-benzimidazole-4-carboxamide;2-cyclopentyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3-methyl-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-2,7-dimethoxy-3H-benzimidazole-4-carboxamide;2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;2-cyclopropyl-N-(2,6-difluorophenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;2-cyclopropyl-N-(2,6-dibromophenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;2-cyclopropyl-N-(2,6-dimethylphenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;2-cyclopropyl-N-(2,4,6-trifluorophenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;2-cyclopropyl-N-(2,6-dichlorophenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;2-cyclopropyl-N-(3,5-dimethyl-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;2-cyclopropyl-N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-3H-benzimidazole-4-carboxamide;N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;2-cyclopropyl-N-(4-carboxy-2,6-dimethylphenyl)-7-methoxy-3H-benzimidazole-4-carboxamide;N-(4-carboxy-2,6-dimethylphenyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;N-(3-chloro-4-pyridyl)-7-methoxy-2-propyl-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-8-methoxy-2-n-propyl-quinoline-5-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide;1-butyloxycarbonyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-1H-indole-6-carboxamide;1-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-3-methyl-N-(4-pyridyl)-1H-indole-6-carboxamide;1-benzyl-N-(4-hydroxyphenyl)-3-methyl-1H-indole-6-carboxamide;1-(2-cyclohexyl)ethyl-3-methyl-N-(4-pyrimidinyl)-1H-indole-6-carboxamide;1-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-N-(3,5-dimethyl-[1,2,4]-triazol-4-yl)-3-methyl-1H-indole-6-carboxamide;1-benzyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indoline-6-carboxamide;1-(2-cyclopentyl-7-methoxy-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone;2-(3,5-dichloro-4-pyridyl)-1-[1-(4-methoxybenzyl)-3-methyl-1H-indol-6-yl]-ethanone;2-(3,5-dichloro-pyridin-4-yl)-1-[1-(1-toluene-4-sulphonyl)-3-methyl-1H-indol-6-yl]-ethanone;1-[1-(4-methoxybenzyl)-3-methyl-1H-indol-6-yl]-2-(4-pyridyl)-ethanone;1-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone;1,3-bis-(4-pyridyl)-2-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-propan-2-ol;7-methoxy-2-methoxymethyl-4-[2-(4-pyridyl)ethyl]-3H-benzimidazole;2-(4-carboxamidobenzyl)-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;[2-(3-chlorophenoxy)-pyridin-3-yl]-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-methanone;2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazole;4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-2-methoxymethyl-3H-benzimidazole;ethyl5-(2-cyclopropyl-7-methoxy-benzimidazole-4-yl)pyridine-2-carboxylate;2-cyclopropyl-7-methoxy-4-(4-morpholinosulphonyl)-3H-benzimidazole;1-benzyl-7-methoxy-2-methoxymethyl-4-(2-(4-pyridyl)-ethyl)-1H-benzimidazole;1-cyclohexylmethyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide;1-(2-cyclohexyl)ethyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide;1-[3-(cyclohexyl)propyl]-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-heptyl-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)methyl-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydrofuran-2-yl)methyl-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(tetrahydro-furan-3-yl)-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3-methoxy)-cyclopentyl-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(5-chloro-thiophen-2-yl)methyl-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3,5-dimethylisoxazol-4-yl)methyl-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(2-methyl-thiazol-4-yl)methyl-1H-indole-6-carboxamide;methyl5-[6-(3,5-dichloro-pyridin-4-ylcarbamoyl)-3-methyl-indol-1-ylmethyl]-furan-2-carboxylate;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)methyl-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(2-morpholin-4-yl)ethyl-1H-indole-6-carboxamide;methyl5-[6-(3,5-dichloro-pyridin-4-ylcarbamoyl)-3-methyl-indole-1-yl]-pentanoate;N-(3,5-dichloro-4-pyridyl)-1-(4-trifluorobenzyl)-3-methyl-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(4-methyl-sulphonylbenzyl)-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-1-(4-methoxycarbonyl-benzyl)-3-methyl-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(3-nitrobenzyl)-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-1-(naphthalen-2-yl)methyl-3-methyl-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-1-(biphenyl-4-yl)methyl-3-methyl-1H-indole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-methyl-1-(1-benzyl-imidazol-2-yl)methyl-1H-indole-6-carboxamide;N-(3,5-dichloro-pyridin-4-yl)-3-ethyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;N-(3,5-dichloro-pyridin-4-yl)-3-isopropyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;N-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxyethyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;N-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxyisopropyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide;N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1H-indole-6-carboxamide;1-benzyl-4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one;4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one;1-(4-methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-ethyl)-1H-indole;cis- andtrans-[1-(4-methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-vinyl)-1H-indole;6-(1-hydroxy-1-phenyl-2-pyridin-4-yl)ethyl-1-(4-methoxybenzyl)-3-methyl-1H-indole;[1-(4-methoxy-benzyl)-3-methyl-1H-indol-6-yl]-phenyl-methanone;N-methoxy-1-(4-methoxybenzyl)-3-methyl-N-methyl-1H-indole-6-carboxamide;1-benzyl-N-(3,5-dichloro-4-pyridyl)-3-methyl-1H-indazole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-1-(4-methoxybenzyl)-3-methyl-1H-indazole-6-carboxamide;N-(3,5-dichloro-4-pyridyl)-4-methoxy-2-methoxymethyl-benzoxazole-7-carboxamide;N-(3,5-dichloro-4-pyridyl)-3-isopropyl-1-methyl-1H-indole-5-carboxamide;and the corresponding pyridine N-oxides, and their prodrugs, andpharmaceutically acceptable salts and solvates thereof.
 36. A compoundaccording to claim 1 selected from the group consisting of:N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;N-(3,5-dichloro-4-pyridyl)-2,7-dimethoxy-3H-benzimidazole-4-carboxamide;2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;2-isopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;2-cyclopropyl-N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-3H-benzimidazole-4-carboxamide;N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazole;4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-2-methoxymethyl-3H-benzimidazole;and the corresponding pyridine N-oxides, and their prodrugs, andpharmaceutically acceptable salts and solvates thereof.
 37. The compoundaccording to claim 1 which is selected from2-Cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazole;and its corresponding pyridine N-oxide, and its prodrugs, andpharmaceutically acceptable salts and solvates thereof.
 38. Apharmaceutical composition comprising an effective amount of a compoundaccording to claim 1 or a prodrug thereof, and pharmaceuticallyacceptable salts and solvates thereof in association with apharmaceutically acceptable carrier or excipient.
 39. A method oftreating a patient suffering from, or subject to, conditions which canbe ameliorated by the administration of an inhibitor of TNF, comprisingadminstering to said patient the compound of formula (I) or a prodrugthereof, and pharmaceutically acceptable salts and solvates thereof asclaimed in claim
 1. 40. A method of treating a patient suffering from,or subject to, conditions which can be ameliorated by the administrationof an inhibitor of type IV cyclic AMP phosphodiesterase, comprisingadministering to said patient the compound of formula (I) or a prodrugthereof, and pharmaceutically acceptable salts and solvates thereof asclaimed in claim
 1. 41. A method of treating a patient suffering from,or subject to, conditions which can be ameliorated by the administrationof an inhibitor of type IV cyclic AMP phosphodiesterase or of TNF,comprising administering to said patient an effective amount of acompound of formula (I) or a prodrug thereof, and pharmaceuticallyacceptable salts and solvates thereof as claimed in claim 1.